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1
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Pretti E, Shell MS. Characterizing the Sequence Landscape of Peptide Fibrillization with a Bottom-Up Coarse-Grained Model. J Phys Chem B 2025; 129:3559-3570. [PMID: 40146906 DOI: 10.1021/acs.jpcb.4c07248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/29/2025]
Abstract
Molecular insight into amyloid aggregation is crucial for understanding the details of protein fibril nucleation and growth, which play a significant role in a wide range of proteinopathies. The length and time scales for fibrillization make its computational study an intrinsically multiscale problem, necessitating the use of coarse-grained modeling. A wide variety of coarse-grained models for peptides have been proposed, often parametrized with a combination of top-down and bottom-up approaches. Here, we present a predictive, sequence-transferable bottom-up coarse-grained model, systematically developed using only information from atomistic simulations by applying an extended-ensemble relative entropy minimization technique. The resulting model is capable of accurately recovering conformational properties of peptides constructed from a reduced alphabet of amino acids, of predicting secondary structures of isolated and interacting peptides from their sequences alone, and of simulating aggregation of peptides that have been experimentally characterized as amyloidogenic. Finally, we couple such coarse-grained simulations with a genetic algorithm to characterize the sequence space of the reduced alphabet and identify features of sequences for which ordered fibrillar states are both thermodynamically favorable and kinetically accessible.
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Affiliation(s)
- Evan Pretti
- Department of Chemical Engineering, Engineering II Building, University of California, Santa Barbara, Santa Barbara, California 93106-5080, United States
| | - M Scott Shell
- Department of Chemical Engineering, Engineering II Building, University of California, Santa Barbara, Santa Barbara, California 93106-5080, United States
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2
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Schuhmann F, Akkaya KC, Puchkov D, Hohensee S, Lehmann M, Liu F, Pezeshkian W. Integrative Molecular Dynamics Simulations Untangle Cross-Linking Data to Unveil Mitochondrial Protein Distributions. Angew Chem Int Ed Engl 2025; 64:e202417804. [PMID: 39644219 DOI: 10.1002/anie.202417804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 11/14/2024] [Accepted: 11/26/2024] [Indexed: 12/09/2024]
Abstract
Cross-linking mass spectrometry (XL-MS) enables the mapping of protein-protein interactions on the cellular level. When applied to all compartments of mitochondria, the sheer number of cross-links and connections can be overwhelming, rendering simple cluster analyses convoluted and uninformative. To address this limitation, we integrate the XL-MS data, 3D electron microscopy data, and localization annotations with a supra coarse-grained molecular dynamics simulation to sort all data, making clusters more accessible and interpretable. In the context of mitochondria, this method, through a total of 6.9 milliseconds of simulations, successfully identifies known, suggests unknown protein clusters, and reveals the distribution of inner mitochondrial membrane proteins allowing a more precise localization within compartments. Our integrative approach suggests, that two so-far ambigiously placed proteins FAM162A and TMEM126A are localized in the cristae, which is validated through super resolution microscopy. Together, this demonstrates the strong potential of the presented approach.
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Affiliation(s)
- Fabian Schuhmann
- Niels Bohr Institute, University of Copenhagen, Blegdamsvej 17, 2100, Copenhagen, Denmark
| | - Kerem Can Akkaya
- Department of Structural Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-Roessle-Str. 10, 13125, Berlin, Germany
- Department of Molecular Physiology and Cell Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-Roessle-Str. 10, 13125, Berlin, Germany
| | - Dmytro Puchkov
- Department of Molecular Physiology and Cell Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-Roessle-Str. 10, 13125, Berlin, Germany
| | - Svea Hohensee
- Department of Molecular Physiology and Cell Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-Roessle-Str. 10, 13125, Berlin, Germany
| | - Martin Lehmann
- Department of Molecular Physiology and Cell Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-Roessle-Str. 10, 13125, Berlin, Germany
| | - Fan Liu
- Department of Structural Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-Roessle-Str. 10, 13125, Berlin, Germany
- Charité - Universitätsmedizin Berlin, Charitépl. 1, 10117, Berlin, Germany
| | - Weria Pezeshkian
- Niels Bohr Institute, University of Copenhagen, Blegdamsvej 17, 2100, Copenhagen, Denmark
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3
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Nadkarni I, Jeong J, Yalcin B, Aluru NR. Modulating Coarse-Grained Dynamics by Perturbing Free Energy Landscapes. J Phys Chem A 2024; 128:10029-10040. [PMID: 39540849 DOI: 10.1021/acs.jpca.4c04530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Abstract
We introduce an approach to describe the long-time dynamics of multiatomic molecules by modulating the free energy landscape (FEL) to capture dominant features of the energy-barrier crossing dynamics of the all-atom (AA) system. Notably, we establish that the self-diffusion coefficient of coarse-grained (CG) systems can be accurately delineated by enhancing conservative force fields with high-frequency perturbations. Using theoretical arguments, we show that these perturbations do not alter the lower-order distribution functions, thereby preserving the structure of the AA system after coarse-graining. We demonstrate the utility of this approach using molecular dynamics simulations of simple molecules in bulk with distinct dynamical characteristics with and without time scale separations as well as for inhomogeneous systems where a fluid is confined in a slit-like nanochannel. Additionally, we also apply our approach to more powerful many-body potentials optimized by using machine learning (ML).
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Affiliation(s)
- Ishan Nadkarni
- Walker Department of Mechanical Engineering, The University of Texas at Austin, Austin, Texas 78712, United States
| | - Jinu Jeong
- Department of Mechanical Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States
| | - Bugra Yalcin
- Oden Institute for Computational Engineering and Sciences, The University of Texas at Austin, Austin, Texas 78712, United States
| | - Narayana R Aluru
- Walker Department of Mechanical Engineering, The University of Texas at Austin, Austin, Texas 78712, United States
- Oden Institute for Computational Engineering and Sciences, The University of Texas at Austin, Austin, Texas 78712, United States
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4
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Ouyang Y, Zhang Z. Advancing high thermal conductivity: novel theories, innovative materials, and applications in thermal management technologies. JOURNAL OF PHYSICS. CONDENSED MATTER : AN INSTITUTE OF PHYSICS JOURNAL 2024; 36:463002. [PMID: 39151465 DOI: 10.1088/1361-648x/ad7086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Accepted: 08/16/2024] [Indexed: 08/19/2024]
Abstract
Effective thermal management is crucial for the performance and stability of modern electronics, emphasizing the demand for high thermal conductivity (κ). This review summarizes the latest development in highκ, discussing the emerging theories, innovative materials and practical applications for interfacial heat dissipation. Unique phononic thermal transport behaviors are discussed, including four phonon-phonon scattering, hydrodynamic phonons, surface phonon-polaritons, and more. The review also highlights innovative materials with highκ, such as two-dimensional pentagonal structures, boron carbon nitrogen structures, hexagonal boron arsenide andθ-phase tantalum nitride. In addition, the potential of polymer composites reinforced with highκfillers and surface engineering for advanced electronic applications are also discussed. By integrating these theoretical approaches and material innovations, this review offers comprehensive strategies for enhancing thermal management in modern electronic devices.
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Affiliation(s)
- Yulou Ouyang
- College of Physics and Electronic Engineering, Hengyang Normal University, Hengyang 421002, People's Republic of China
| | - Zhongwei Zhang
- Center for Phononics and Thermal Energy Science, China-EU Joint Lab for Nanophononics, MOE Key Laboratory of Advanced Micro-structured Materials, School of Physics Science and Engineering, Tongji University, Shanghai 200092, People's Republic of China
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5
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Del Razo MJ, Crommelin D, Bolhuis PG. Data-driven dynamical coarse-graining for condensed matter systems. J Chem Phys 2024; 160:024108. [PMID: 38193550 DOI: 10.1063/5.0177553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 12/05/2023] [Indexed: 01/10/2024] Open
Abstract
Simulations of condensed matter systems often focus on the dynamics of a few distinguished components but require integrating the full system. A prime example is a molecular dynamics simulation of a (macro)molecule in a solution, where the molecule(s) and the solvent dynamics need to be integrated, rendering the simulations computationally costly and often unfeasible for physically/biologically relevant time scales. Standard coarse graining approaches can reproduce equilibrium distributions and structural features but do not properly include the dynamics. In this work, we develop a general data-driven coarse-graining methodology inspired by the Mori-Zwanzig formalism, which shows that macroscopic systems with a large number of degrees of freedom can be described by a few relevant variables and additional noise and memory terms. Our coarse-graining method consists of numerical integrators for the distinguished components, where the noise and interaction terms with other system components are substituted by a random variable sampled from a data-driven model. The model is parameterized using data from multiple short-time full-system simulations, and then, it is used to run long-time simulations. Applying our methodology to three systems-a distinguished particle under a harmonic and a bistable potential and a dimer with two metastable configurations-the resulting coarse-grained models are capable of reproducing not only the equilibrium distributions but also the dynamic behavior due to temporal correlations and memory effects. Remarkably, our method even reproduces the transition dynamics between metastable states, which is challenging to capture correctly. Our approach is not constrained to specific dynamics and can be extended to systems beyond Langevin dynamics, and, in principle, even to non-equilibrium dynamics.
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Affiliation(s)
- Mauricio J Del Razo
- Department of Mathematics and Computer Science, Freie Universität Berlin, Berlin, Germany
- Van't Hoff Institute for Molecular Sciences, University of Amsterdam, PO Box 94157, 1090GD Amsterdam, The Netherlands
- Korteweg-de Vries Institute for Mathematics, University of Amsterdam, PO Box 94248, 1090GD Amsterdam, The Netherlands
- Dutch Institute for Emergent Phenomena, University of Amsterdam, Amsterdam, The Netherlands
| | - Daan Crommelin
- Korteweg-de Vries Institute for Mathematics, University of Amsterdam, PO Box 94248, 1090GD Amsterdam, The Netherlands
- Centrum Wiskunde & Informatica, 1098 XG Amsterdam, The Netherlands
| | - Peter G Bolhuis
- Van't Hoff Institute for Molecular Sciences, University of Amsterdam, PO Box 94157, 1090GD Amsterdam, The Netherlands
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6
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Zheng W, Liu X. Modeling and Simulation of the NMDA Receptor at Coarse-Grained and Atomistic Levels. Methods Mol Biol 2024; 2799:269-280. [PMID: 38727913 DOI: 10.1007/978-1-0716-3830-9_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/01/2024]
Abstract
N-Methyl-D-aspartate (NMDA) receptors are glutamate-gated excitatory channels that play essential roles in brain functions. While high-resolution structures were solved for an allosterically inhibited form of functional NMDA receptor, other key functional states (particularly the active open-channel state) have not yet been resolved at atomic resolutions. To decrypt the molecular mechanism of the NMDA receptor activation, structural modeling and simulation are instrumental in providing detailed information about the dynamics and energetics of the receptor in various functional states. In this chapter, we describe coarse-grained modeling of the NMDA receptor using an elastic network model and related modeling/analysis tools (e.g., normal mode analysis, flexibility and hotspot analysis, cryo-EM flexible fitting, and transition pathway modeling) based on available structures. Additionally, we show how to build an atomistic model of the active-state receptor with targeted molecular dynamics (MD) simulation and explore its energetics and dynamics with conventional MD simulation. Taken together, these modeling and simulation can offer rich structural and dynamic information which will guide experimental studies of the activation of this key receptor.
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Affiliation(s)
- Wenjun Zheng
- Department of Physics, State University of New York at Buffalo, Buffalo, NY, USA.
| | - Xing Liu
- Department of Physics, State University of New York at Buffalo, Buffalo, NY, USA
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7
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Wu J, Xue W, Voth GA. K-Means Clustering Coarse-Graining (KMC-CG): A Next Generation Methodology for Determining Optimal Coarse-Grained Mappings of Large Biomolecules. J Chem Theory Comput 2023; 19:8987-8997. [PMID: 37957028 PMCID: PMC10720621 DOI: 10.1021/acs.jctc.3c01053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 10/25/2023] [Accepted: 10/27/2023] [Indexed: 11/21/2023]
Abstract
Coarse-grained (CG) molecular dynamics (MD) has become a method of choice for simulating various large scale biomolecular processes; therefore, the systematic definition of the CG mappings for biomolecules remains an important topic. Appropriate CG mappings can significantly enhance the representability of a CG model and improve its ability to capture critical features of large biomolecules. In this work, we present a systematic and more generalized method called K-means clustering coarse-graining (KMC-CG), which builds on the earlier approach of essential dynamics coarse-graining (ED-CG). KMC-CG removes the sequence-dependent constraints of ED-CG, allowing it to explore a more extensive space and thus enabling the discovery of more physically optimal CG mappings. Furthermore, the implementation of the K-means clustering algorithm can variationally optimize the CG mapping with efficiency and stability. This new method is tested in three cases: ATP-bound G-actin, the HIV-1 CA pentamer, and the Arp2/3 complex. In these examples, the CG models generated by KMC-CG are seen to better capture the structural, dynamic, and functional domains. KMC-CG therefore provides a robust and consistent approach to generating CG models of large biomolecules that can then be more accurately parametrized by either bottom-up or top-down CG force fields.
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Affiliation(s)
| | | | - Gregory A. Voth
- Department of Chemistry,
Chicago Center for Theoretical Chemistry, The James Franck Institute,
and Institute for Biophysical Dynamics, The University of Chicago, Chicago, Illinois 60637, United States
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8
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Nadkarni I, Wu H, Aluru NR. Data-Driven Approach to Coarse-Graining Simple Liquids in Confinement. J Chem Theory Comput 2023; 19:7358-7370. [PMID: 37791529 DOI: 10.1021/acs.jctc.3c00633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/05/2023]
Abstract
We propose a data-driven framework for identifying coarse-grained (CG) Lennard-Jones (LJ) potential parameters in confined systems for simple liquids. Our approach involves the use of a Deep Neural Network (DNN) that is trained to approximate the solution of the Inverse Liquid State (ILST) problem for confined systems. The DNN model inherently incorporates essential physical characteristics specific to confined fluids, enabling an accurate prediction of inhomogeneity effects. By utilizing transfer learning, we predict single-site LJ potentials of simple multiatomic liquids confined in a slit-like channel, which effectively replicate both the fluid structure and molecular force of the target All-Atom (AA) system when the electrostatic interactions are not dominant. In addition, we showcase the synergy between the data-driven approach and the well-known Bottom-Up coarse-graining method utilizing Relative-Entropy (RE) Minimization. Through the sequential utilization of these two methods, the robustness of the iterative RE method is significantly augmented, leading to a remarkable enhancement in convergence.
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Affiliation(s)
- Ishan Nadkarni
- Walker Department of Mechanical Engineering, The University of Texas at Austin, Austin, Texas 78712, United States
| | - Haiyi Wu
- Oden Institute for Computational Engineering and Sciences, The University of Texas at Austin, Austin, Texas 78712, United States
| | - Narayana R Aluru
- Walker Department of Mechanical Engineering, The University of Texas at Austin, Austin, Texas 78712, United States
- Oden Institute for Computational Engineering and Sciences, The University of Texas at Austin, Austin, Texas 78712, United States
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9
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Mohammadi E, Joshi SY, Deshmukh SA. Development, Validation, and Applications of Nonbonded Interaction Parameters between Coarse-Grained Amino Acid and Water Models. Biomacromolecules 2023; 24:4078-4092. [PMID: 37603467 DOI: 10.1021/acs.biomac.3c00441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/23/2023]
Abstract
Interactions between amino acids and water play an important role in determining the stability and folding/unfolding, in aqueous solution, of many biological macromolecules, which affects their function. Thus, understanding the molecular-level interactions between water and amino acids is crucial to tune their function in aqueous solutions. Herein, we have developed nonbonded interaction parameters between the coarse-grained (CG) models of 20 amino acids and the one-site CG water model. The nonbonded parameters, represented using the 12-6 Lennard Jones (LJ) potential form, have been optimized using an artificial neural network (ANN)-assisted particle swarm optimization (PSO) (ANN-assisted PSO) method. All-atom (AA) molecular dynamics (MD) simulations of dipeptides in TIP3P water molecules were performed to calculate the Gibbs hydration free energies. The nonbonded force-field (FF) parameters between CG amino acids and the one-site CG water model were developed to accurately reproduce these energies. Furthermore, to test the transferability of these newly developed parameters, we calculated the hydration free energies of the analogues of the amino acid side chains, which showed good agreement with reported experimental data. Additionally, we show the applicability of these models by performing self-assembly simulations of peptide amphiphiles. Overall, these models are transferable and can be used to study the self-assembly of various biomaterials and biomolecules to develop a mechanistic understanding of these processes.
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Affiliation(s)
- Esmat Mohammadi
- Department of Chemical Engineering, Virginia Tech, Blacksburg, Virginia 24061, United States
| | - Soumil Y Joshi
- Department of Chemical Engineering, Virginia Tech, Blacksburg, Virginia 24061, United States
| | - Sanket A Deshmukh
- Department of Chemical Engineering, Virginia Tech, Blacksburg, Virginia 24061, United States
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10
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Sahrmann P, Loose TD, Durumeric AEP, Voth GA. Utilizing Machine Learning to Greatly Expand the Range and Accuracy of Bottom-Up Coarse-Grained Models through Virtual Particles. J Chem Theory Comput 2023; 19:4402-4413. [PMID: 36802592 PMCID: PMC10373655 DOI: 10.1021/acs.jctc.2c01183] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Indexed: 02/22/2023]
Abstract
Coarse-grained (CG) models parametrized using atomistic reference data, i.e., "bottom up" CG models, have proven useful in the study of biomolecules and other soft matter. However, the construction of highly accurate, low resolution CG models of biomolecules remains challenging. We demonstrate in this work how virtual particles, CG sites with no atomistic correspondence, can be incorporated into CG models within the context of relative entropy minimization (REM) as latent variables. The methodology presented, variational derivative relative entropy minimization (VD-REM), enables optimization of virtual particle interactions through a gradient descent algorithm aided by machine learning. We apply this methodology to the challenging case of a solvent-free CG model of a 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) lipid bilayer and demonstrate that introduction of virtual particles captures solvent-mediated behavior and higher-order correlations which REM alone cannot capture in a more standard CG model based only on the mapping of collections of atoms to the CG sites.
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Affiliation(s)
- Patrick
G. Sahrmann
- Department of Chemistry, Chicago Center
for Theoretical Chemistry, James Franck Institute, and Institute for
Biophysical Dynamics, The University of
Chicago, Chicago, Illinois 60637, United
States
| | - Timothy D. Loose
- Department of Chemistry, Chicago Center
for Theoretical Chemistry, James Franck Institute, and Institute for
Biophysical Dynamics, The University of
Chicago, Chicago, Illinois 60637, United
States
| | - Aleksander E. P. Durumeric
- Department of Chemistry, Chicago Center
for Theoretical Chemistry, James Franck Institute, and Institute for
Biophysical Dynamics, The University of
Chicago, Chicago, Illinois 60637, United
States
| | - Gregory A. Voth
- Department of Chemistry, Chicago Center
for Theoretical Chemistry, James Franck Institute, and Institute for
Biophysical Dynamics, The University of
Chicago, Chicago, Illinois 60637, United
States
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11
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Sedinkin SL, Burns D, Shukla D, Potoyan DA, Venditti V. Solution Structure Ensembles of the Open and Closed Forms of the ∼130 kDa Enzyme I via AlphaFold Modeling, Coarse Grained Simulations, and NMR. J Am Chem Soc 2023; 145:13347-13356. [PMID: 37278728 PMCID: PMC10772991 DOI: 10.1021/jacs.3c03425] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Large-scale interdomain rearrangements are essential to protein function, governing the activity of large enzymes and molecular machineries. Yet, obtaining an atomic-resolution understanding of how the relative domain positioning is affected by external stimuli is a hard task in modern structural biology. Here, we show that combining structural modeling by AlphaFold2 with coarse-grained molecular dynamics simulations and NMR residual dipolar coupling data is sufficient to characterize the spatial domain organization of bacterial enzyme I (EI), a ∼130 kDa multidomain oligomeric protein that undergoes large-scale conformational changes during its catalytic cycle. In particular, we solve conformational ensembles for EI at two different experimental temperatures and demonstrate that a lower temperature favors sampling of the catalytically competent closed state of the enzyme. These results suggest a role for conformational entropy in the activation of EI and demonstrate the ability of our protocol to detect and characterize the effect of external stimuli (such as mutations, ligand binding, and post-translational modifications) on the interdomain organization of multidomain proteins. We expect the ensemble refinement protocol described here to be easily transferrable to the investigation of the structure and dynamics of other uncharted multidomain systems and have assembled a Google Colab page (https://potoyangroup.github.io/Seq2Ensemble/) to facilitate implementation of the presented methodology elsewhere.
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Affiliation(s)
| | - Daniel Burns
- Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, Iowa 50011, USA
| | - Divyanshu Shukla
- Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA
| | - Davit A. Potoyan
- Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA
- Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, Iowa 50011, USA
| | - Vincenzo Venditti
- Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA
- Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, Iowa 50011, USA
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12
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Galata AA, Kröger M. Globular Proteins and Where to Find Them within a Polymer Brush-A Case Study. Polymers (Basel) 2023; 15:polym15102407. [PMID: 37242983 DOI: 10.3390/polym15102407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 05/15/2023] [Accepted: 05/19/2023] [Indexed: 05/28/2023] Open
Abstract
Protein adsorption by polymerized surfaces is an interdisciplinary topic that has been approached in many ways, leading to a plethora of theoretical, numerical and experimental insight. There is a wide variety of models trying to accurately capture the essence of adsorption and its effect on the conformations of proteins and polymers. However, atomistic simulations are case-specific and computationally demanding. Here, we explore universal aspects of the dynamics of protein adsorption through a coarse-grained (CG) model, that allows us to explore the effects of various design parameters. To this end, we adopt the hydrophobic-polar (HP) model for proteins, place them uniformly at the upper bound of a CG polymer brush whose multibead-spring chains are tethered to a solid implicit wall. We find that the most crucial factor affecting the adsorption efficiency appears to be the polymer grafting density, while the size of the protein and its hydrophobicity ratio come also into play. We discuss the roles of ligands and attractive tethering surfaces to the primary adsorption as well as secondary and ternary adsorption in the presence of attractive (towards the hydrophilic part of the protein) beads along varying spots of the backbone of the polymer chains. The percentage and rate of adsorption, density profiles and the shapes of the proteins, alongside with the respective potential of mean force are recorded to compare the various scenarios during protein adsorption.
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Affiliation(s)
- Aikaterini A Galata
- Magnetism and Interface Physics, Department of Materials, ETH Zurich, CH-8093 Zurich, Switzerland
| | - Martin Kröger
- Magnetism and Interface Physics, Department of Materials, ETH Zurich, CH-8093 Zurich, Switzerland
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13
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Dragelj J, Karafoulidi-Retsou C, Katz S, Lenz O, Zebger I, Caserta G, Sacquin-Mora S, Mroginski MA. Conformational and mechanical stability of the isolated large subunit of membrane-bound [NiFe]-hydrogenase from Cupriavidus necator. Front Microbiol 2023; 13:1073315. [PMID: 36733774 PMCID: PMC9886862 DOI: 10.3389/fmicb.2022.1073315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 12/23/2022] [Indexed: 01/18/2023] Open
Abstract
Comprising at least a bipartite architecture, the large subunit of [NiFe]-hydrogenase harbors the catalytic nickel-iron site while the small subunit houses an array of electron-transferring Fe-S clusters. Recently, some [NiFe]-hydrogenase large subunits have been isolated showing an intact and redox active catalytic cofactor. In this computational study we have investigated one of these metalloproteins, namely the large subunit HoxG of the membrane-bound hydrogenase from Cupriavidus necator (CnMBH), targeting its conformational and mechanical stability using molecular modelling and long all-atom Gaussian accelerated molecular dynamics (GaMD). Our simulations predict that isolated HoxG is stable in aqueous solution and preserves a large portion of its mechanical properties, but loses rigidity in regions around the active site, in contrast to the MBH heterodimer. Inspired by biochemical data showing dimerization of the HoxG protein and IR measurements revealing an increased stability of the [NiFe] cofactor in protein preparations with higher dimer content, corresponding simulations of homodimeric forms were also undertaken. While the monomeric subunit contains several flexible regions, our data predicts a regained rigidity in homodimer models. Furthermore, we computed the electrostatic properties of models obtained by enhanced sampling with GaMD, which displays a significant amount of positive charge at the protein surface, especially in solvent-exposed former dimer interfaces. These data offer novel insights on the way the [NiFe] core is protected from de-assembly and provide hints for enzyme anchoring to surfaces, which is essential information for further investigations on these minimal enzymes.
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Affiliation(s)
- Jovan Dragelj
- Institut für Chemie, Technische Universität Berlin, Berlin, Germany
| | | | - Sagie Katz
- Institut für Chemie, Technische Universität Berlin, Berlin, Germany
| | - Oliver Lenz
- Institut für Chemie, Technische Universität Berlin, Berlin, Germany
| | - Ingo Zebger
- Institut für Chemie, Technische Universität Berlin, Berlin, Germany
| | - Giorgio Caserta
- Institut für Chemie, Technische Universität Berlin, Berlin, Germany
| | - Sophie Sacquin-Mora
- Institut für Chemie, Technische Universität Berlin, Berlin, Germany
- CNRS, UPR, Laboratoire de Biochimie Théorique, Université de Paris Cité, Paris, France
- Institut de Biologie Physico-Chimique-Fondation Edmond de Rotschild, PSL Research University, Paris, France
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14
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George A, Kim DN, Moser T, Gildea IT, Evans JE, Cheung MS. Graph identification of proteins in tomograms (GRIP-Tomo). Protein Sci 2023; 32:e4538. [PMID: 36482866 PMCID: PMC9798246 DOI: 10.1002/pro.4538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 11/23/2022] [Accepted: 12/03/2022] [Indexed: 12/14/2022]
Abstract
In this study, we present a method of pattern mining based on network theory that enables the identification of protein structures or complexes from synthetic volume densities, without the knowledge of predefined templates or human biases for refinement. We hypothesized that the topological connectivity of protein structures is invariant, and they are distinctive for the purpose of protein identification from distorted data presented in volume densities. Three-dimensional densities of a protein or a complex from simulated tomographic volumes were transformed into mathematical graphs as observables. We systematically introduced data distortion or defects such as missing fullness of data, the tumbling effect, and the missing wedge effect into the simulated volumes, and varied the distance cutoffs in pixels to capture the varying connectivity between the density cluster centroids in the presence of defects. A similarity score between the graphs from the simulated volumes and the graphs transformed from the physical protein structures in point data was calculated by comparing their network theory order parameters including node degrees, betweenness centrality, and graph densities. By capturing the essential topological features defining the heterogeneous morphologies of a network, we were able to accurately identify proteins and homo-multimeric complexes from 10 topologically distinctive samples without realistic noise added. Our approach empowers future developments of tomogram processing by providing pattern mining with interpretability, to enable the classification of single-domain protein native topologies as well as distinct single-domain proteins from multimeric complexes within noisy volumes.
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Affiliation(s)
- August George
- Environmental Molecular Sciences LaboratoryPacific Northwest National LaboratoryRichlandWashingtonUSA
- Department of Biomedical EngineeringOregon Health & Science UniversityPortlandOregonUSA
| | - Doo Nam Kim
- Biological Science DivisionPacific Northwest National LaboratoryRichlandWashingtonUSA
| | - Trevor Moser
- Environmental Molecular Sciences LaboratoryPacific Northwest National LaboratoryRichlandWashingtonUSA
| | - Ian T. Gildea
- Environmental Molecular Sciences LaboratoryPacific Northwest National LaboratoryRichlandWashingtonUSA
| | - James E. Evans
- Environmental Molecular Sciences LaboratoryPacific Northwest National LaboratoryRichlandWashingtonUSA
- School of Biological SciencesWashington State UniversityPullmanWashingtonUSA
| | - Margaret S. Cheung
- Environmental Molecular Sciences LaboratoryPacific Northwest National LaboratoryRichlandWashingtonUSA
- Department of PhysicsUniversity of WashingtonSeattleWashingtonUSA
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15
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Avalos JB, Lísal M, Larentzos JP, Mackie AD, Brennan JK. Generalized Energy-Conserving Dissipative Particle Dynamics with Mass Transfer. Part 1: Theoretical Foundation and Algorithm. J Chem Theory Comput 2022; 18:7639-7652. [PMID: 36306139 DOI: 10.1021/acs.jctc.2c00452] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
An extension of the generalized energy-conserving dissipative particle dynamics method (GenDPDE) that allows mass transfer between mesoparticles via a diffusion process is presented. By considering the concept of the mesoparticles as property carriers, the complexity and flexibility of the GenDPDE framework were enhanced to allow for interparticle mass transfer under isoenergetic conditions, notated here as GenDPDE-M. In the formulation, diffusion is described via the theory of mesoscale irreversible processes based on linear relationships between the fluxes and thermodynamic forces, where their fluctuations are described by Langevin-like equations. The mass exchange between mesoparticles is such that the mass of the mesoparticle remains unchanged after the transfer process and requires additional considerations regarding the coupling with other system properties such as the particle internal energy. The proof-of-concept work presented in this article is the first part of a two-part article series. In Part 1, the development of the GenDPDE-M theoretical framework and the derivation of the algorithm are presented in detail. Part 2 of this article series is targeted for practitioners, where applications, demonstrations, and practical considerations for implementing the GenDPDE-M method are presented and discussed.
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Affiliation(s)
- Josep Bonet Avalos
- Department d'Enginyeria Química, ETSEQ, Universitat Rovira i Virgili, Tarragona 43007 Spain
| | - Martin Lísal
- Department of Molecular and Mesoscopic Modeling, The Czech Academy of Sciences, Institute of Chemical Process Fundamentals, Prague 165 01 Czech Republic.,Department of Physics, Faculty of Science, J. E. Purkyně University, Ústí nad Labem, 40096 Czech Republic
| | - James P Larentzos
- U.S. Army Combat Capabilities Development Command (DEVCOM) Army Research Laboratory, Aberdeen Proving Ground, Maryland 21005 United States
| | - Allan D Mackie
- Department d'Enginyeria Química, ETSEQ, Universitat Rovira i Virgili, Tarragona 43007 Spain
| | - John K Brennan
- U.S. Army Combat Capabilities Development Command (DEVCOM) Army Research Laboratory, Aberdeen Proving Ground, Maryland 21005 United States
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16
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Unravelling viral dynamics through molecular dynamics simulations - A brief overview. Biophys Chem 2022; 291:106908. [DOI: 10.1016/j.bpc.2022.106908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 09/28/2022] [Accepted: 10/05/2022] [Indexed: 11/24/2022]
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17
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Depta PN, Dosta M, Wenzel W, Kozlowska M, Heinrich S. Hierarchical Coarse-Grained Strategy for Macromolecular Self-Assembly: Application to Hepatitis B Virus-Like Particles. Int J Mol Sci 2022; 23:ijms232314699. [PMID: 36499027 PMCID: PMC9740473 DOI: 10.3390/ijms232314699] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 11/01/2022] [Accepted: 11/14/2022] [Indexed: 11/27/2022] Open
Abstract
Macromolecular self-assembly is at the basis of many phenomena in material and life sciences that find diverse applications in technology. One example is the formation of virus-like particles (VLPs) that act as stable empty capsids used for drug delivery or vaccine fabrication. Similarly to the capsid of a virus, VLPs are protein assemblies, but their structural formation, stability, and properties are not fully understood, especially as a function of the protein modifications. In this work, we present a data-driven modeling approach for capturing macromolecular self-assembly on scales beyond traditional molecular dynamics (MD), while preserving the chemical specificity. Each macromolecule is abstracted as an anisotropic object and high-dimensional models are formulated to describe interactions between molecules and with the solvent. For this, data-driven protein-protein interaction potentials are derived using a Kriging-based strategy, built on high-throughput MD simulations. Semi-automatic supervised learning is employed in a high performance computing environment and the resulting specialized force-fields enable a significant speed-up to the micrometer and millisecond scale, while maintaining high intermolecular detail. The reported generic framework is applied for the first time to capture the formation of hepatitis B VLPs from the smallest building unit, i.e., the dimer of the core protein HBcAg. Assembly pathways and kinetics are analyzed and compared to the available experimental observations. We demonstrate that VLP self-assembly phenomena and dependencies are now possible to be simulated. The method developed can be used for the parameterization of other macromolecules, enabling a molecular understanding of processes impossible to be attained with other theoretical models.
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Affiliation(s)
- Philipp Nicolas Depta
- Institute of Solids Process Engineering and Particle Technology (SPE), Hamburg University of Technology, 21073 Hamburg, Germany
- Correspondence:
| | - Maksym Dosta
- Institute of Solids Process Engineering and Particle Technology (SPE), Hamburg University of Technology, 21073 Hamburg, Germany
- Boehringer Ingelheim Pharma GmbH & Co Kg., 88400 Biberach an der Riss, Germany
| | - Wolfgang Wenzel
- Institute of Nanotechnology (INT), Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany
| | - Mariana Kozlowska
- Institute of Nanotechnology (INT), Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany
| | - Stefan Heinrich
- Institute of Solids Process Engineering and Particle Technology (SPE), Hamburg University of Technology, 21073 Hamburg, Germany
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18
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Scott L, Borissova A, Di Renzo A, Ghadiri M. Application of coarse-graining for large scale simulation of fluid and particle motion in spiral jet mill by CFD-DEM. POWDER TECHNOL 2022. [DOI: 10.1016/j.powtec.2022.117962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
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19
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Chu K, Chen Y, Ji L, Zhou Z, Yu A, Chen J. Coarse-grained CFD-DEM study of Gas-solid flow in gas cyclone. Chem Eng Sci 2022. [DOI: 10.1016/j.ces.2022.117906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
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20
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Magi Meconi G, Sasselli IR, Bianco V, Onuchic JN, Coluzza I. Key aspects of the past 30 years of protein design. REPORTS ON PROGRESS IN PHYSICS. PHYSICAL SOCIETY (GREAT BRITAIN) 2022; 85:086601. [PMID: 35704983 DOI: 10.1088/1361-6633/ac78ef] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 06/15/2022] [Indexed: 06/15/2023]
Abstract
Proteins are the workhorse of life. They are the building infrastructure of living systems; they are the most efficient molecular machines known, and their enzymatic activity is still unmatched in versatility by any artificial system. Perhaps proteins' most remarkable feature is their modularity. The large amount of information required to specify each protein's function is analogically encoded with an alphabet of just ∼20 letters. The protein folding problem is how to encode all such information in a sequence of 20 letters. In this review, we go through the last 30 years of research to summarize the state of the art and highlight some applications related to fundamental problems of protein evolution.
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Affiliation(s)
- Giulia Magi Meconi
- Computational Biophysics Lab, Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA), Paseo de Miramon 182, 20014, Donostia-San Sebastián, Spain
| | - Ivan R Sasselli
- Computational Biophysics Lab, Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA), Paseo de Miramon 182, 20014, Donostia-San Sebastián, Spain
| | | | - Jose N Onuchic
- Center for Theoretical Biological Physics, Department of Physics & Astronomy, Department of Chemistry, Department of Biosciences, Rice University, Houston, TX 77251, United States of America
| | - Ivan Coluzza
- BCMaterials, Basque Center for Materials, Applications and Nanostructures, Bld. Martina Casiano, UPV/EHU Science Park, Barrio Sarriena s/n, 48940 Leioa, Spain
- Basque Foundation for Science, Ikerbasque, 48009, Bilbao, Spain
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21
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Karibayev M, Kalybekkyzy S, Wang Y, Mentbayeva A. Molecular Modeling in Anion Exchange Membrane Research: A Brief Review of Recent Applications. Molecules 2022; 27:3574. [PMID: 35684512 PMCID: PMC9182285 DOI: 10.3390/molecules27113574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/24/2022] [Accepted: 05/30/2022] [Indexed: 12/04/2022] Open
Abstract
Anion Exchange Membrane (AEM) fuel cells have attracted growing interest, due to their encouraging advantages, including high power density and relatively low cost. AEM is a polymer matrix, which conducts hydroxide (OH-) ions, prevents physical contact of electrodes, and has positively charged head groups (mainly quaternary ammonium (QA) groups), covalently bound to the polymer backbone. The chemical instability of the quaternary ammonium (QA)-based head groups, at alkaline pH and elevated temperature, is a significant threshold in AEMFC technology. This review work aims to introduce recent studies on the chemical stability of various QA-based head groups and transportation of OH- ions in AEMFC, via modeling and simulation techniques, at different scales. It starts by introducing the fundamental theories behind AEM-based fuel-cell technology. In the main body of this review, we present selected computational studies that deal with the effects of various parameters on AEMs, via a variety of multi-length and multi-time-scale modeling and simulation methods. Such methods include electronic structure calculations via the quantum Density Functional Theory (DFT), ab initio, classical all-atom Molecular Dynamics (MD) simulations, and coarse-grained MD simulations. The explored processing and structural parameters include temperature, hydration levels, several QA-based head groups, various types of QA-based head groups and backbones, etc. Nowadays, many methods and software packages for molecular and materials modeling are available. Applications of such methods may help to understand the transportation mechanisms of OH- ions, the chemical stability of functional head groups, and many other relevant properties, leading to a performance-based molecular and structure design as well as, ultimately, improved AEM-based fuel cell performances. This contribution aims to introduce those molecular modeling methods and their recent applications to the AEM-based fuel cells research community.
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Affiliation(s)
- Mirat Karibayev
- Department of Chemical & Materials Engineering, School of Engineering and Digital Sciences, Nazarbayev University, Nur-Sultan 010000, Kazakhstan;
| | - Sandugash Kalybekkyzy
- Laboratory of Advanced Materials and Systems for Energy Storage, Center for Energy and Advanced Materials Science, National Laboratory Astana, Nazarbayev University, Nur-Sultan 010000, Kazakhstan;
| | - Yanwei Wang
- Department of Chemical & Materials Engineering, School of Engineering and Digital Sciences, Nazarbayev University, Nur-Sultan 010000, Kazakhstan;
- Laboratory of Computational Materials Science for Energy Applications, Center for Energy and Advanced Materials Science, National Laboratory Astana, Nur-Sultan 010000, Kazakhstan
| | - Almagul Mentbayeva
- Department of Chemical & Materials Engineering, School of Engineering and Digital Sciences, Nazarbayev University, Nur-Sultan 010000, Kazakhstan;
- Laboratory of Advanced Materials and Systems for Energy Storage, Center for Energy and Advanced Materials Science, National Laboratory Astana, Nazarbayev University, Nur-Sultan 010000, Kazakhstan;
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22
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Hernández-Del-Valle M, Valencia-Expósito A, López-Izquierdo A, Casanova-Ferrer P, Tarazona P, Martín-Bermudo MD, Míguez DG. A coarse-grained approach to model the dynamics of the actomyosin cortex. BMC Biol 2022; 20:90. [PMID: 35459165 PMCID: PMC9034637 DOI: 10.1186/s12915-022-01279-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Accepted: 03/11/2022] [Indexed: 01/21/2023] Open
Abstract
Background The dynamics of the actomyosin machinery is at the core of many important biological processes. Several relevant cellular responses such as the rhythmic compression of the cell cortex are governed, at a mesoscopic level, by the nonlinear interaction between actin monomers, actin crosslinkers, and myosin motors. Coarse-grained models are an optimal tool to study actomyosin systems, since they can include processes that occur at long time and space scales, while maintaining the most relevant features of the molecular interactions. Results Here, we present a coarse-grained model of a two-dimensional actomyosin cortex, adjacent to a three-dimensional cytoplasm. Our simplified model incorporates only well-characterized interactions between actin monomers, actin crosslinkers and myosin, and it is able to reproduce many of the most important aspects of actin filament and actomyosin network formation, such as dynamics of polymerization and depolymerization, treadmilling, network formation, and the autonomous oscillatory dynamics of actomyosin. Conclusions We believe that the present model can be used to study the in vivo response of actomyosin networks to changes in key parameters of the system, such as alterations in the attachment of actin filaments to the cell cortex. Supplementary Information The online version contains supplementary material available at (10.1186/s12915-022-01279-2).
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Affiliation(s)
- Miguel Hernández-Del-Valle
- Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Madrid, 28049, Spain.,IFIMAC, Fac. de Ciencias, Universidad Autónoma de Madrid, Madrid, 28049, Spain.,Instituto Nicolás Cabrera, Fac. de Ciencias, Universidad Autónoma de Madrid, Madrid, 28049, Spain.,Fisica de la Materia Condensada, Fac. de Ciencias, Universidad Autónoma de Madrid, Madrid, 28049, Spain
| | - Andrea Valencia-Expósito
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide/CSIC/JA, Carretera de Utrera km 1, Seville, 41013, Spain
| | - Antonio López-Izquierdo
- Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Madrid, 28049, Spain.,IFIMAC, Fac. de Ciencias, Universidad Autónoma de Madrid, Madrid, 28049, Spain.,Instituto Nicolás Cabrera, Fac. de Ciencias, Universidad Autónoma de Madrid, Madrid, 28049, Spain.,Fisica de la Materia Condensada, Fac. de Ciencias, Universidad Autónoma de Madrid, Madrid, 28049, Spain
| | - Pau Casanova-Ferrer
- Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Madrid, 28049, Spain.,IFIMAC, Fac. de Ciencias, Universidad Autónoma de Madrid, Madrid, 28049, Spain.,Instituto Nicolás Cabrera, Fac. de Ciencias, Universidad Autónoma de Madrid, Madrid, 28049, Spain.,Fisica de la Materia Condensada, Fac. de Ciencias, Universidad Autónoma de Madrid, Madrid, 28049, Spain
| | - Pedro Tarazona
- IFIMAC, Fac. de Ciencias, Universidad Autónoma de Madrid, Madrid, 28049, Spain.,Instituto Nicolás Cabrera, Fac. de Ciencias, Universidad Autónoma de Madrid, Madrid, 28049, Spain.,Fisica Teórica de la Materia Condensada, Fac. de Ciencias, Universidad Autónoma de Madrid, Madrid, 28049, Spain
| | - Maria D Martín-Bermudo
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide/CSIC/JA, Carretera de Utrera km 1, Seville, 41013, Spain
| | - David G Míguez
- Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Madrid, 28049, Spain. .,IFIMAC, Fac. de Ciencias, Universidad Autónoma de Madrid, Madrid, 28049, Spain. .,Instituto Nicolás Cabrera, Fac. de Ciencias, Universidad Autónoma de Madrid, Madrid, 28049, Spain. .,Fisica de la Materia Condensada, Fac. de Ciencias, Universidad Autónoma de Madrid, Madrid, 28049, Spain.
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23
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Karaca E, Prévost C, Sacquin-Mora S. Modeling the Dynamics of Protein-Protein Interfaces, How and Why? Molecules 2022; 27:1841. [PMID: 35335203 PMCID: PMC8950966 DOI: 10.3390/molecules27061841] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 03/06/2022] [Accepted: 03/08/2022] [Indexed: 12/07/2022] Open
Abstract
Protein-protein assemblies act as a key component in numerous cellular processes. Their accurate modeling at the atomic level remains a challenge for structural biology. To address this challenge, several docking and a handful of deep learning methodologies focus on modeling protein-protein interfaces. Although the outcome of these methods has been assessed using static reference structures, more and more data point to the fact that the interaction stability and specificity is encoded in the dynamics of these interfaces. Therefore, this dynamics information must be taken into account when modeling and assessing protein interactions at the atomistic scale. Expanding on this, our review initially focuses on the recent computational strategies aiming at investigating protein-protein interfaces in a dynamic fashion using enhanced sampling, multi-scale modeling, and experimental data integration. Then, we discuss how interface dynamics report on the function of protein assemblies in globular complexes, in fuzzy complexes containing intrinsically disordered proteins, as well as in active complexes, where chemical reactions take place across the protein-protein interface.
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Affiliation(s)
- Ezgi Karaca
- Izmir Biomedicine and Genome Center, Izmir 35340, Turkey;
- Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir 35340, Turkey
| | - Chantal Prévost
- CNRS, Laboratoire de Biochimie Théorique, UPR9080, Université de Paris, 13 rue Pierre et Marie Curie, 75005 Paris, France;
- Institut de Biologie Physico-Chimique, Fondation Edmond de Rothschild, PSL Research University, 75006 Paris, France
| | - Sophie Sacquin-Mora
- CNRS, Laboratoire de Biochimie Théorique, UPR9080, Université de Paris, 13 rue Pierre et Marie Curie, 75005 Paris, France;
- Institut de Biologie Physico-Chimique, Fondation Edmond de Rothschild, PSL Research University, 75006 Paris, France
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24
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Ma B, Zhang Z, Li Y, Lin X, Gu N. Evaluation of Interactions between SARS-CoV-2 RBD and Full-Length ACE2 with Coarse-Grained Molecular Dynamics Simulations. J Chem Inf Model 2022; 62:936-944. [PMID: 35147419 PMCID: PMC8862743 DOI: 10.1021/acs.jcim.1c01306] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Indexed: 12/13/2022]
Abstract
Compared to all-atom models, coarse-grained models enable the investigation of the dynamics of simulation systems on a much larger length scale and a longer time scale, which makes them suitable for studying macromolecular systems. Hence, in this work, we performed multiple μs-scale Martini coarse-grained molecular dynamics simulations to reveal the interaction details between SARS-CoV-2 RBD and full-length human ACE2. Besides, the key coarse-grained systems were backmapped into the corresponding all-atom system for the display of structural details. Our results indicated that the plier structure in two ends of the binding interface plays a key role in the binding process of SARS-CoV-2 RBD with ACE2. Furthermore, we also found that when there is no B0AT1 in the simulation system, the N-terminus of ACE2 is more likely to approach the cell membrane, which has a strong correlation with the subsequent fusion of the virus with the cell membrane. These binding details of SARS-CoV-2 RBD and the ACE2 protease domain (PD) as well as the membrane orientation thermodynamics can promote the development of therapeutic drugs and preventive vaccines against SARS-CoV-2.
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Affiliation(s)
- Baocai Ma
- State
Key Laboratory of Bioelectronics, Jiangsu Key Laboratory for Biomaterials
and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, P. R. China
- Collaborative
Innovation Center of Suzhou Nano-Science and Technology, Suzhou Key Laboratory of Biomaterials and Technologies, Suzhou 215123, P. R. China
| | - Zuoheng Zhang
- State
Key Laboratory of Bioelectronics, Jiangsu Key Laboratory for Biomaterials
and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, P. R. China
- Collaborative
Innovation Center of Suzhou Nano-Science and Technology, Suzhou Key Laboratory of Biomaterials and Technologies, Suzhou 215123, P. R. China
| | - Yan Li
- State
Key Laboratory of Bioelectronics, Jiangsu Key Laboratory for Biomaterials
and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, P. R. China
- Collaborative
Innovation Center of Suzhou Nano-Science and Technology, Suzhou Key Laboratory of Biomaterials and Technologies, Suzhou 215123, P. R. China
| | - Xubo Lin
- Beijing
Advanced Innovation Center for Biomedical Engineering, School of Engineering
Medicine, Beihang University, Beijing 100191, P. R. China
| | - Ning Gu
- State
Key Laboratory of Bioelectronics, Jiangsu Key Laboratory for Biomaterials
and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, P. R. China
- Collaborative
Innovation Center of Suzhou Nano-Science and Technology, Suzhou Key Laboratory of Biomaterials and Technologies, Suzhou 215123, P. R. China
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25
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Bourassin N, Barbault F, Baaden M, Sacquin-Mora S. Between Two Walls: Modeling the Adsorption Behavior of β-Glucosidase A on Bare and SAM-Functionalized Gold Surfaces. LANGMUIR : THE ACS JOURNAL OF SURFACES AND COLLOIDS 2022; 38:1313-1323. [PMID: 35050631 DOI: 10.1021/acs.langmuir.1c01774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
The efficient immobilization of enzymes on surfaces remains a complex but central issue in the biomaterials field, which requires us to understand this process at the atomic level. Using a multiscale approach combining all-atom molecular dynamics and coarse-grain Brownian dynamics simulations, we investigated the adsorption behavior of β-glucosidase A (βGA) on bare and self-assembled monolayer (SAM)-functionalized gold surfaces. We monitored the enzyme position and orientation during the molecular dynamics (MD) trajectories and measured the contacts it forms with both surfaces. While the adsorption process has little impact on the protein conformation, it can nonetheless perturb its mechanical properties and catalytic activity. Our results show that compared to the SAM-functionalized surface, the adsorption of βGA on bare gold is more stable, but less specific, and more likely to disrupt the enzyme's function. This observation emphasizes the fact that the structural organization of proteins at the solid interface is a key point when designing devices based on enzyme immobilization, as one must find an acceptable stability-activity trade-off.
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Affiliation(s)
- Nicolas Bourassin
- Laboratoire de Biochimie Théorique, UPR 9080, Université de Paris, CNRS, 13 rue Pierre et Marie Curie, 75005 Paris, France
- Institut de Biologie Physico-Chimique-Fondation Edmond de Rothschild, PSL Research University, 75005 Paris, France
| | | | - Marc Baaden
- Laboratoire de Biochimie Théorique, UPR 9080, Université de Paris, CNRS, 13 rue Pierre et Marie Curie, 75005 Paris, France
- Institut de Biologie Physico-Chimique-Fondation Edmond de Rothschild, PSL Research University, 75005 Paris, France
| | - Sophie Sacquin-Mora
- Laboratoire de Biochimie Théorique, UPR 9080, Université de Paris, CNRS, 13 rue Pierre et Marie Curie, 75005 Paris, France
- Institut de Biologie Physico-Chimique-Fondation Edmond de Rothschild, PSL Research University, 75005 Paris, France
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26
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Kameda T, Awazu A, Togashi Y. Molecular dynamics analysis of biomolecular systems including nucleic acids. Biophys Physicobiol 2022; 19:e190027. [DOI: 10.2142/biophysico.bppb-v19.0027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 08/18/2022] [Indexed: 12/01/2022] Open
Affiliation(s)
| | - Akinori Awazu
- Graduate School of Integrated Sciences for Life, Hiroshima University
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27
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Mishra RP, Goel G. Multiscale Model for Quantitative Prediction of Insulin Aggregation Nucleation Kinetics. J Chem Theory Comput 2021; 17:7886-7898. [PMID: 34813303 DOI: 10.1021/acs.jctc.1c00499] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
We combined kinetic, thermodynamic, and structural information from single-molecule (protein folding) and two-molecule (association) explicit-solvent simulations for determination of kinetic parameters in protein aggregation nucleation with insulin as the model protein. A structural bioinformatics approach was developed to account for heterogeneity of aggregation-prone species, with the transition complex theory found applicable in modeling association kinetics involving non-native species. Specifically, the kinetic pathway for formation of aggregation-prone oligomeric species was found to contain a structurally specific dominant binding mode, making the kinetic process similar to native protein association. The kinetic parameters thus obtained were used in a population balance model, and accurate predictions for aggregation nucleation time varying over 2 orders of magnitude with changes in either insulin concentration or an aggregation-inhibitor ligand concentration were obtained, while an empirical parameter set was not found to be transferable for prediction of ligand effects. Further, this physically determined kinetic parameter set provided several mechanistic insights, such as identification of the rate-limiting step in aggregation nucleation and a quantitative explanation for the switch from Arrhenius to non-Arrhenius aggregation kinetics around the melting temperature of insulin.
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Affiliation(s)
- Rit Pratik Mishra
- Department of Chemical Engineering, Indian Institute of Technology Delhi, Hauz Khas, Delhi 110016, India
| | - Gaurav Goel
- Department of Chemical Engineering, Indian Institute of Technology Delhi, Hauz Khas, Delhi 110016, India
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Vaiwala R, Ayappa KG. A generic force field for simulating native protein structures using dissipative particle dynamics. SOFT MATTER 2021; 17:9772-9785. [PMID: 34651150 DOI: 10.1039/d1sm01194d] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
A coarse-grained force field for molecular dynamics simulations of the native structures of proteins in a dissipative particle dynamics (DPD) framework is developed. The parameters for bonded interactions are derived by mapping the bonds and angles for 20 amino acids onto target distributions obtained from fully atomistic simulations in explicit solvent. A dual-basin potential is introduced for stabilizing backbone angles, to cover a wide spectrum of protein secondary structures. The backbone dihedral potential enables folding of the protein from an unfolded initial state to the folded native structure. The proposed force field is validated by evaluating the structural properties of several model peptides and proteins including the SARS-CoV-2 fusion peptide, consisting of α-helices, β-sheets, loops and turns. Detailed comparisons with fully atomistic simulations are carried out to assess the ability of the proposed force field to stabilize the different secondary structures present in proteins. The compact conformations of the native states were evident from the radius of gyration and the high intensity peaks of the root mean square deviation histograms, which were found to be within 0.4 nm. The Ramachandran-like energy landscape on the phase space of backbone angles (θ) and dihedrals (ϕ) effectively captured the conformational phase space of α-helices at ∼(ϕ = 50°,θ = 90°) and β-strands at ∼(ϕ = ±180°,θ = 90-120°). Furthermore, the residue-residue native contacts were also well reproduced by the proposed DPD model. The applicability of the model to multidomain complexes was assessed using lysozyme and a large α-helical bacterial pore-forming toxin, cytolysin A. Our study illustrates that the proposed force field is generic, and can potentially be extended for efficient in silico investigations of membrane bound polypeptides and proteins using DPD simulations.
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Affiliation(s)
- Rakesh Vaiwala
- Department of Chemical Engineering, Indian Institute of Science, Bangalore 560012, India.
| | - K Ganapathy Ayappa
- Department of Chemical Engineering, Indian Institute of Science, Bangalore 560012, India.
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India
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Yasuda T, Morita R, Shigeta Y, Harada R. Independent Nontargeted Parallel Cascade Selection Molecular Dynamics (Ino-PaCS-MD) to Enhance the Conformational Sampling of Proteins. J Chem Theory Comput 2021; 17:5933-5943. [PMID: 34410106 DOI: 10.1021/acs.jctc.1c00558] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Biological functions are related to long-time protein dynamics (rare events) that are induced over microseconds. Such protein dynamics can be investigated using molecular dynamics (MD) simulations. However, the detection of rare events remains challenging using conventional MD (cMD) since the accessible timescales of cMD are shorter than those of the biological functions. Recently, the parallel cascade selection MD (PaCS-MD) has been proposed to detect such rare events, wherein transition paths are generated between a given reactant and product. As an extension, the nontargeted PaCS-MD (nt-PaCS-MD) has been proposed to predict the transition paths without requiring reference to any product. Thus, as a further extension, we herein propose independent nt-PaCS-MD, namely, Ino-PaCS-MD, wherein multiple walkers are launched from a set of different starting configurations. Each walker repeats a cycle of restarting short-time MD simulations from configurations with high potentials for making transitions to neighboring metastable states. To further enhance the sampling ability, Ino-PaCS-MD temporarily stops the conformational search and periodically resets the starting configurations so that they are uniformly distributed in a conformational subspace, thereby preventing a given protein from being trapped in one of the metastable states. As a demonstration, Ino-PaCS-MD successfully detects rare events of a maltose-binding protein as open-close transitions with a nanosecond-order simulation time, although a microsecond-order cMD simulation failed to detect these rare events, showing the high sampling efficiency of Ino-PaCS-MD.
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Affiliation(s)
- Takunori Yasuda
- College of Biological Sciences, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-0821, Japan
| | - Rikuri Morita
- Center for Computational Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan
| | - Yasuteru Shigeta
- Center for Computational Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan
| | - Ryuhei Harada
- Center for Computational Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan
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30
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Liwo A, Czaplewski C, Sieradzan AK, Lipska AG, Samsonov SA, Murarka RK. Theory and Practice of Coarse-Grained Molecular Dynamics of Biologically Important Systems. Biomolecules 2021; 11:1347. [PMID: 34572559 PMCID: PMC8465211 DOI: 10.3390/biom11091347] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 09/03/2021] [Accepted: 09/09/2021] [Indexed: 12/16/2022] Open
Abstract
Molecular dynamics with coarse-grained models is nowadays extensively used to simulate biomolecular systems at large time and size scales, compared to those accessible to all-atom molecular dynamics. In this review article, we describe the physical basis of coarse-grained molecular dynamics, the coarse-grained force fields, the equations of motion and the respective numerical integration algorithms, and selected practical applications of coarse-grained molecular dynamics. We demonstrate that the motion of coarse-grained sites is governed by the potential of mean force and the friction and stochastic forces, resulting from integrating out the secondary degrees of freedom. Consequently, Langevin dynamics is a natural means of describing the motion of a system at the coarse-grained level and the potential of mean force is the physical basis of the coarse-grained force fields. Moreover, the choice of coarse-grained variables and the fact that coarse-grained sites often do not have spherical symmetry implies a non-diagonal inertia tensor. We describe selected coarse-grained models used in molecular dynamics simulations, including the most popular MARTINI model developed by Marrink's group and the UNICORN model of biological macromolecules developed in our laboratory. We conclude by discussing examples of the application of coarse-grained molecular dynamics to study biologically important processes.
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Affiliation(s)
- Adam Liwo
- Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, Poland; (C.C.); (A.K.S.); (A.G.L.); (S.A.S.)
| | - Cezary Czaplewski
- Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, Poland; (C.C.); (A.K.S.); (A.G.L.); (S.A.S.)
| | - Adam K. Sieradzan
- Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, Poland; (C.C.); (A.K.S.); (A.G.L.); (S.A.S.)
| | - Agnieszka G. Lipska
- Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, Poland; (C.C.); (A.K.S.); (A.G.L.); (S.A.S.)
| | - Sergey A. Samsonov
- Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, Poland; (C.C.); (A.K.S.); (A.G.L.); (S.A.S.)
| | - Rajesh K. Murarka
- Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal Bypass Road, Bhopal 462066, MP, India;
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31
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Luo S, Thachuk M. Conservative Potentials for a Lattice-Mapped Coarse-Grained Scheme. J Phys Chem A 2021; 125:6486-6497. [PMID: 34264666 DOI: 10.1021/acs.jpca.1c02000] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The conservative potential, arising from a coarse-grain (CG) mapping scheme for nonbonded atomistic particles, is studied. This is a bottom-up approach from first-principles that maps atomistic particles to fluid element-like subcells whose centers lie on a regular, cubic lattice. Unlike standard CG mapping schemes, the current one uses dynamic labeling which on-the-fly changes the CG labels of the particles. The subcells can also be different sizes and shapes, in principle. Equilibrium atomistic molecular dynamics trajectories for different Lennard-Jones fluids are calculated and converted to CG ones, from which CG probability distribution functions are calculated. Correlation studies show position and mass CG variables are uncoupled in a given subcell, as are different vector components of position. Furthermore, the strongest coupling occurs with neighboring cells in specific directions, and the resulting distribution is well described by a multivariate Gaussian. This implies the CG potential has a generalized quadratic form, whose derivative can be determined analytically. A microscopic rationalization is provided for the signs and relative magnitudes of different correlation coefficients, and in some cases, a connection is made with bulk properties of the fluid. We argue the generalized quadratic form should be robust to changes in the particulars of the CG scheme, as well as the nature of the atomistic intermolecular potential. Only a few potential parameters need to be calculated from the underlying atomistic system. This is significant because it indicates the transferability of this form to other, more complex systems. This transferability will be tested in future work, where mapping schemes with fuzzy boundaries will be considered.
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Affiliation(s)
- Siwei Luo
- Department of Chemistry, University of British Columbia,Vancouver V6T 1Z1, Canada
| | - Mark Thachuk
- Department of Chemistry, University of British Columbia,Vancouver V6T 1Z1, Canada
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32
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Abstract
It is a great challenge to develop ultra-coarse-grained models in simulations of biological macromolecules. In this study, the original coarse-graining strategy proposed in our previous work [M. Li and J. Z. H. Zhang, Phys. Chem. Chem. Phys. 23, 8926 (2021)] is first extended to the ultra-coarse-graining (UCG) modeling of liquid water, with the NC increasing from 4-10 to 20-500. The UCG force field is parameterized by the top-down strategy and subsequently refined on important properties of liquid water by the trial-and-error scheme. The optimal cutoffs for non-bonded interactions in the NC = 20/100/500 UCG simulations are, respectively, determined on energy convergence. The results show that the average density at 300 K can be accurately reproduced from the well-refined UCG models while it is largely different in describing compressibility, self-diffusion coefficient, etc. The density-temperature relationships predicted by these UCG models are in good agreement with the experiment result. Besides, two polarizable states of the UCG molecules are observed after simulated systems are equilibrated. The ion-water RDFs from the ion-involved NC = 100 UCG simulation are nearly in accord with the scaled AA ones. Furthermore, the concentration of ions can influence the ratio of two polarizable states in the NC = 100 simulation. Finally, it is illustrated that the proposed UCG models can accelerate liquid water simulation by 114-135 times, compared with the TIP3P force field. The proposed UCG force field is simple, generic, and transferable, potentially providing valuable information for UCG simulations of large biomolecules.
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Affiliation(s)
- Min Li
- College of Physics, Qingdao University, Qingdao, Shandong 266071, People's Republic of China
| | - WenCai Lu
- College of Physics, Qingdao University, Qingdao, Shandong 266071, People's Republic of China
| | - John ZengHui Zhang
- School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, People's Republic of China
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33
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Fernández Del Río B, Rey A. Behavior of Proteins under Pressure from Experimental Pressure-Dependent Structures. J Phys Chem B 2021; 125:6179-6191. [PMID: 34100621 PMCID: PMC8478274 DOI: 10.1021/acs.jpcb.1c03313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Structure-based models are coarse-grained representations of the interactions responsible for the protein folding process. In their simplest form, they use only the native contact map of a given protein to predict the main features of its folding process by computer simulation. Given their limitations, these models are frequently complemented with sequence-dependent contributions or additional information. Specifically, to analyze the effect of pressure on the folding/unfolding transition, special forms of these interaction potentials are employed, which may a priori determine the outcome of the simulations. In this work, we have tried to keep the original simplicity of structure-based models. Therefore, we have used folded structures that have been experimentally determined at different pressures to define native contact maps and thus interactions dependent on pressure. Despite the apparently tiny structural differences induced by pressure, our simulation results provide different thermodynamic and kinetic behaviors, which roughly correspond to experimental observations (when there is a possible comparison) of two proteins used as benchmarks, hen egg-white lysozyme and dihydrofolate reductase. Therefore, this work shows the feasibility of using experimental native structures at different pressures to analyze the global effects of this physical property on the protein folding process.
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Affiliation(s)
- Beatriz Fernández Del Río
- Departamento de Química Física, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain
| | - Antonio Rey
- Departamento de Química Física, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain
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34
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Sousa AA, Schuck P, Hassan SA. Biomolecular interactions of ultrasmall metallic nanoparticles and nanoclusters. NANOSCALE ADVANCES 2021; 3:2995-3027. [PMID: 34124577 PMCID: PMC8168927 DOI: 10.1039/d1na00086a] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 04/16/2021] [Indexed: 05/03/2023]
Abstract
The use of nanoparticles (NPs) in biomedicine has made a gradual transition from proof-of-concept to clinical applications, with several NP types meeting regulatory approval or undergoing clinical trials. A new type of metallic nanostructures called ultrasmall nanoparticles (usNPs) and nanoclusters (NCs), while retaining essential properties of the larger (classical) NPs, have features common to bioactive proteins. This combination expands the potential use of usNPs and NCs to areas of diagnosis and therapy traditionally reserved for small-molecule medicine. Their distinctive physicochemical properties can lead to unique in vivo behaviors, including improved renal clearance and tumor distribution. Both the beneficial and potentially deleterious outcomes (cytotoxicity, inflammation) can, in principle, be controlled through a judicious choice of the nanocore shape and size, as well as the chemical ligands attached to the surface. At present, the ability to control the behavior of usNPs is limited, partly because advances are still needed in nanoengineering and chemical synthesis to manufacture and characterize ultrasmall nanostructures and partly because our understanding of their interactions in biological environments is incomplete. This review addresses the second limitation. We review experimental and computational methods currently available to understand molecular mechanisms, with particular attention to usNP-protein complexation, and highlight areas where further progress is needed. We discuss approaches that we find most promising to provide relevant molecular-level insight for designing usNPs with specific behaviors and pave the way to translational applications.
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Affiliation(s)
- Alioscka A Sousa
- Department of Biochemistry, Federal University of São Paulo São Paulo SP 04044 Brazil
| | - Peter Schuck
- National Institute of Biomedical Imaging and Bioengineering, NIH Bethesda MD 20892 USA
| | - Sergio A Hassan
- BCBB, National Institute of Allergy and Infectious Diseases, NIH Bethesda MD 20892 USA
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35
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Li M, Zhang JZH. Multiscale polarizable coarse-graining water models on cluster-level electrostatic dipoles. Phys Chem Chem Phys 2021; 23:8926-8935. [PMID: 33876052 DOI: 10.1039/d1cp00338k] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
The development of a coarse-grained (CG) water model is increasingly important in CG studies of biological processes. In this work, we developed a generic CG force field of liquid water on cluster-level electrostatic dipoles. An exponential term is introduced in the non-bonded potential to adjust the well depth. The whole force field is parametrized on the AMOEBA simulation and then refined on the experimental density, dielectric permittivity and isothermal compressibility. The new CG water force field is suitable for the construction of multi-resolution water models and here the NC = 4/5/10 systems are taken as examples. The results show that the NC = 4/5/10 models can correctly reproduce the density and relative dielectric permittivity. The models can well predict the pressure-density/density-temperature relationships close to the all-atom or experiment results. However, the new models behave differently from other CG models in several water properties such as the air-water surface tension. Through dipole distributions, two representative polarizable configurations are captured after the NC = 4/5/10 systems are dynamically equilibrated. Besides, the NC = 4 model is coupled with the Martini Na+/Cl- models to predict ion-relevant radial distribution functions in comparison to the Martini result. Lastly, CPU tests suggest that the new CG models can enhance simulation efficiency by factors of 20-42, compared to the TIP3P force field. The newly proposed polarizable water force field is practical and transferable and can be flexibly extended to higher coarse-graining of liquid water.
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Affiliation(s)
- Min Li
- College of Physics, Qingdao University, Qingdao, Shandong 266071, P. R. China.
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36
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Zheng W, Wen H. Predicting lipid and ligand binding sites in TRPV1 channel by molecular dynamics simulation and machine learning. Proteins 2021; 89:966-977. [PMID: 33739482 DOI: 10.1002/prot.26075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 02/25/2021] [Accepted: 03/15/2021] [Indexed: 11/06/2022]
Abstract
As a key cellular sensor, the TRPV1 channel undergoes a gating transition from a closed state to an open state in response to many physical and chemical stimuli. This transition is regulated by small-molecule ligands including lipids and various agonists/antagonists, but the underlying molecular mechanisms remain obscure. Thanks to recent revolution in cryo-electron microscopy, a growing list of new structures of TRPV1 and other TRPV channels have been solved in complex with various ligands including lipids. Toward elucidating how ligand binding correlates with TRPV1 gating, we have performed extensive molecular dynamics simulations (with cumulative time of 20 μs), starting from high-resolution structures of TRPV1 in both the closed and open states. By comparing between the open and closed state ensembles, we have identified state-dependent binding sites for small-molecule ligands in general and lipids in particular. We further use machine learning to predict top ligand-binding sites as important features to classify the closed vs open states. The predicted binding sites are thoroughly validated by matching homologous sites in all structures of TRPV channels bound to lipids and other ligands, and with previous functional/mutational studies of ligand binding in TRPV1. Taken together, this study has integrated rich structural, dynamic, and functional data to inform future design of small-molecular drugs targeting TRPV1.
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Affiliation(s)
- Wenjun Zheng
- Department of Physics, State University of New York at Buffalo, Buffalo, New York, USA
| | - Han Wen
- Department of Physics, State University of New York at Buffalo, Buffalo, New York, USA
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37
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Mahmood MI, Poma AB, Okazaki KI. Optimizing Gō-MARTINI Coarse-Grained Model for F-BAR Protein on Lipid Membrane. Front Mol Biosci 2021; 8:619381. [PMID: 33693028 PMCID: PMC7937874 DOI: 10.3389/fmolb.2021.619381] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 01/14/2021] [Indexed: 12/31/2022] Open
Abstract
Coarse-grained (CG) molecular dynamics (MD) simulations allow us to access much larger length and time scales than atomistic MD simulations, providing an attractive alternative to the conventional simulations. Based on the well-known MARTINI CG force field, the recently developed Gō-MARTINI model for proteins describes large-amplitude structural dynamics, which has not been possible with the commonly used elastic network model. Using the Gō-MARTINI model, we conduct MD simulations of the F-BAR Pacsin1 protein on lipid membrane. We observe that structural changes of the non-globular protein are largely dependent on the definition of the native contacts in the Gō model. To address this issue, we introduced a simple cutoff scheme and tuned the cutoff distance of the native contacts and the interaction strength of the Lennard-Jones potentials in the Gō-MARTINI model. With the optimized Gō-MARTINI model, we show that it reproduces structural fluctuations of the Pacsin1 dimer from atomistic simulations. We also show that two Pacsin1 dimers properly assemble through lateral interaction on the lipid membrane. Our work presents a first step towards describing membrane remodeling processes in the Gō-MARTINI CG framework by simulating a crucial step of protein assembly on the membrane.
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Affiliation(s)
- Md Iqbal Mahmood
- Department of Theoretical and Computational Molecular Science, Institute for Molecular Science, National Institutes of Natural Sciences, Okazaki, Japan
| | - Adolfo B Poma
- Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland
| | - Kei-Ichi Okazaki
- Department of Theoretical and Computational Molecular Science, Institute for Molecular Science, National Institutes of Natural Sciences, Okazaki, Japan
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38
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Medina E, R Latham D, Sanabria H. Unraveling protein's structural dynamics: from configurational dynamics to ensemble switching guides functional mesoscale assemblies. Curr Opin Struct Biol 2021; 66:129-138. [PMID: 33246199 PMCID: PMC7965259 DOI: 10.1016/j.sbi.2020.10.016] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 10/16/2020] [Accepted: 10/19/2020] [Indexed: 12/18/2022]
Abstract
Evidence regarding protein structure and function manifest the imperative role that dynamics play in proteins, underlining reconsideration of the unanimated sequence-to-structure-to-function paradigm. Structural dynamics portray a heterogeneous energy landscape described by conformational ensembles where each structural representation can be responsible for unique functions or enable macromolecular assemblies. Using the human p27/Cdk2/Cyclin A ternary complex as an example, we highlight the vital role of intramolecular and intermolecular dynamics for target recognition, binding, and inhibition as a critical modulator of cell division. Rapidly sampling configurations is critical for the population of different conformational ensembles encoding functional roles. To garner this knowledge, we present how the integration of (sub)ensemble and single-molecule fluorescence spectroscopy with molecular dynamic simulations can characterize structural dynamics linking the heterogeneous ensembles to function. The incorporation of dynamics into the sequence-to-structure-to-function paradigm promises to assist in tackling various challenges, including understanding the formation and regulation of mesoscale assemblies inside cells.
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Affiliation(s)
- Exequiel Medina
- Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Las Palmeras 3425, Casilla 653, Santiago 7800003, Chile; Department of Physics and Astronomy, Clemson University, Clemson 29634, United States
| | - Danielle R Latham
- Department of Physics and Astronomy, Clemson University, Clemson 29634, United States
| | - Hugo Sanabria
- Department of Physics and Astronomy, Clemson University, Clemson 29634, United States.
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39
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Shang X, Guan Z, Zhang S, Shi L, You H. Predicting the aptamer SYL3C-EpCAM complex's structure with the Martini-based simulation protocol. Phys Chem Chem Phys 2021; 23:7066-7079. [PMID: 33496283 DOI: 10.1039/d0cp05003b] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Aptamers (small single strand DNA/RNAs) such as SYL3C are considered as ideal alternatives to antibodies in cancer related research studies. However, 3D structure predictions for aptamers and aptamer-protein complexes are scarce due to the high cost of experimental measurements and unreliable computer-based methods. Thus aptamers' diagnostic and therapeutic applications are severely restricted. To meet the challenge, we proposed a Martini-based aptamer-protein complex prediction protocol. By combining the base-base contact map from simulation and secondary structure prediction from various tools, improved secondary structure predictions can be obtained. This method reduced the risk of providing incorrect or incomplete base pairs in secondary structure prediction. Thus 3D structure modeling based on the secondary structure can be more reliable. We introduced the soft elastic network to the hairpin folded regions of the Martini ssDNAs to preserve their canonical structure. Using our protocol, we predicted the first 3D structure of the aptamer SYL3C and the SYL3C-EpCAM complex. We believe that our work could contribute to the future aptamer-related research studies and medical implications.
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Affiliation(s)
- Xu Shang
- State Key Laboratory of Computer Architecture, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, 100190, China.
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40
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Xian Y, Xie Y, Silva SM, Karki CB, Qiu W, Li L. StructureMan: A Structure Manipulation Tool to Study Large Scale Biomolecular Interactions. Front Mol Biosci 2021; 7:627087. [PMID: 33505991 PMCID: PMC7831659 DOI: 10.3389/fmolb.2020.627087] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 12/10/2020] [Indexed: 11/22/2022] Open
Abstract
Studying biomolecular interactions is a crucial but challenging task. Due to their large scales, many biomolecular interactions are difficult to be simulated via all atom models. An effective approach to investigate the biomolecular interactions is highly demanded in many areas. Here we introduce a Structure Manipulation (StructureMan) program to operate the structures when studying the large-scale biomolecular interactions. This novel StructureMan tool provides comprehensive operations which can be utilized to study the interactions in various large biological systems. Combining with electrostatic calculation programs such as DelPhi and DelPhiForce, StructureMan was implemented to reveal the detailed electrostatic features in two large biological examples, the viral capsid and molecular motor-microtubule complexes. Applications on these two examples revealed interesting binding mechanisms in the viral capsid and molecular motor. Such applications demonstrated that the StructureMan can be widely used when studying the biomolecular interactions in large scale biological problems. This novel tool provides an alternative approach to efficiently study the biomolecular interactions, especially for large scale biology systems. The StructureMan tool is available at our website: http://compbio.utep.edu/static/downloads/script-for-munipulation2.zip.
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Affiliation(s)
- Yuejiao Xian
- Department of Chemistry and Biochemistry, University of Texas at El Paso, El Paso, TX, United States
| | - Yixin Xie
- Computational Science Program, University of Texas at El Paso, El Paso, TX, United States
| | - Sebastian Miki Silva
- Department of Physics, University of Texas at El Paso, El Paso, TX, United States
| | - Chitra B Karki
- Computational Science Program, University of Texas at El Paso, El Paso, TX, United States
| | - Weihong Qiu
- Department of Physics, Oregon State University, Corvallis, OR, United States.,Department of Biochemistry & Biophysics, Oregon State University, Corvallis, OR, United States
| | - Lin Li
- Computational Science Program, University of Texas at El Paso, El Paso, TX, United States.,Department of Physics, University of Texas at El Paso, El Paso, TX, United States
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41
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Schmidt M, Schroeder I, Bauer D, Thiel G, Hamacher K. Inferring functional units in ion channel pores via relative entropy. EUROPEAN BIOPHYSICS JOURNAL : EBJ 2021; 50:37-57. [PMID: 33523249 PMCID: PMC7872957 DOI: 10.1007/s00249-020-01480-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 10/11/2020] [Accepted: 11/09/2020] [Indexed: 11/25/2022]
Abstract
Coarse-grained protein models approximate the first-principle physical potentials. Among those modeling approaches, the relative entropy framework yields promising and physically sound results, in which a mapping from the target protein structure and dynamics to a model is defined and subsequently adjusted by an entropy minimization of the model parameters. Minimization of the relative entropy is equivalent to maximization of the likelihood of reproduction of (configurational ensemble) observations by the model. In this study, we extend the relative entropy minimization procedure beyond parameter fitting by a second optimization level, which identifies the optimal mapping to a (dimension-reduced) topology. We consider anisotropic network models of a diverse set of ion channels and assess our findings by comparison to experimental results.
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Affiliation(s)
- Michael Schmidt
- Department of Physics, TU Darmstadt, Karolinenpl. 5, 64289 Darmstadt, Germany
| | - Indra Schroeder
- Department of Biology, TU Darmstadt, Schnittspahnstr. 10, 64287 Darmstadt, Germany
| | - Daniel Bauer
- Department of Biology, TU Darmstadt, Schnittspahnstr. 10, 64287 Darmstadt, Germany
| | - Gerhard Thiel
- Department of Biology, TU Darmstadt, Schnittspahnstr. 10, 64287 Darmstadt, Germany
| | - Kay Hamacher
- Department of Physics, Department of Biology, Department of Computer Science, TU Darmstadt, Schnittspahnstr. 10, 64287 Darmstadt, Germany
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42
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Li M, Lu W, Zhang JZ. A three-point coarse-grained model of five-water cluster with permanent dipoles and quadrupoles. Phys Chem Chem Phys 2020; 22:26289-26298. [PMID: 33174895 DOI: 10.1039/d0cp04782a] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
As coarse-grained (CG) studies of large biomolecules increase, developments of reliable CG solvent models become particularly important. In this work, we reduce five water molecules into a three-point CG model with permanent dipole and quadrupole moments. In the CG force field, the modified Morse potential is utilized and an ideal three-water cluster is designed to derive CG-level permanent multipoles. The new CG model is parametrized on the AMOEBA polarizable force field. Various important properties of liquid water are examined to validate the new CG model. Results show that the new CG model can correctly reproduce certain important experimental properties such as density, isothermal compressibility and relative static dielectric permittivity, even better than the existing AA models. Additionally, the CPU tests reveal that the CG model can accelerate molecular dynamics simulations by a factor of 19 compared to the popular AA force field. Compared with the fix-point-charge model widely used in other CG models, the permanent-multipole-based CG model describes more rigid electrostatic attractions. This study also illustrates that the permanent multipole moments contribute a lot to the electrostatic calculations in CG simulation.
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Affiliation(s)
- Min Li
- College of Physics, Qingdao University, Qingdao, Shandong 266071, P. R. China.
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43
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Foley S, Deserno M. Stabilizing Leaflet Asymmetry under Differential Stress in a Highly Coarse-Grained Lipid Membrane Model. J Chem Theory Comput 2020; 16:7195-7206. [PMID: 33126796 DOI: 10.1021/acs.jctc.0c00862] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
We present a version of the coarse-grained Cooke lipid model, modified to simulate asymmetric lipid membranes. It is inspired by a method employed by Wang et al. [ Commun. Comput. Phys. 2013, 13, 1093-1106] for artificially penalizing lipid flip-flop but copes more robustly with differential stress, at the cost of one additional bead per lipid and the concomitant increase in computational overhead. Bilayer asymmetry ultimately breaks down beyond a system size dependent critical differential stress, which can be predicted from a simple analytical model. We remeasure many important material parameters for the new model and find it to be consistent with typical fluid lipid membranes. Maintaining a stable stress asymmetry has many applications, and we give two examples: (i) connecting monolayer stress to lipid number asymmetry in order to directly measure the monolayer area modulus and (ii) finding its strain-dependent higher-order correction by monitoring the equilibrium bilayer area.
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Affiliation(s)
- Samuel Foley
- Department of Physics, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, United States
| | - Markus Deserno
- Department of Physics, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, United States
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44
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Chakravorty A, Higham J, Henchman RH. Entropy of Proteins Using Multiscale Cell Correlation. J Chem Inf Model 2020; 60:5540-5551. [PMID: 32955869 DOI: 10.1021/acs.jcim.0c00611] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
A new multiscale method is presented to calculate the entropy of proteins from molecular dynamics simulations. Termed Multiscale Cell Correlation (MCC), the method decomposes the protein into sets of rigid-body units based on their covalent-bond connectivity at three levels of hierarchy: molecule, residue, and united atom. It evaluates the vibrational and topographical entropy from forces, torques, and dihedrals at each level, taking into account correlations between sets of constituent units that together make up a larger unit at the coarser length scale. MCC gives entropies in close agreement with normal-mode analysis and smaller than those using quasiharmonic analysis as well as providing much faster convergence. Moreover, MCC provides an insightful decomposition of entropy at each length scale and for each type of amino acid according to their solvent exposure and whether they are terminal residues. While the residue entropy depends weakly on solvent exposure, there is greater variation in entropy components for larger, more polar amino acids, which have increased conformational entropy but reduced vibrational entropy with greater solvent exposure.
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Affiliation(s)
- Arghya Chakravorty
- Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Jonathan Higham
- MRC Human Genetics Unit, Institute of Genetics & Molecular Medicine, The University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, United Kingdom
| | - Richard H Henchman
- Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, United Kingdom.,Department of Chemistry, The University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom
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45
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Bourassin N, Baaden M, Lojou E, Sacquin-Mora S. Implicit Modeling of the Impact of Adsorption on Solid Surfaces for Protein Mechanics and Activity with a Coarse-Grained Representation. J Phys Chem B 2020; 124:8516-8523. [PMID: 32924507 DOI: 10.1021/acs.jpcb.0c05347] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Surface immobilized enzymes play a key role in numerous biotechnological applications such as biosensors, biofuel cells, or biocatalytic synthesis. As a consequence, the impact of adsorption on the enzyme structure, dynamics, and function needs to be understood on the molecular level as it is critical for the improvement of these technologies. With this perspective in mind, we used a theoretical approach for investigating local protein flexibility on the residue scale that couples a simplified protein representation with an elastic network and Brownian dynamics simulations. The impact of protein adsorption on a solid surface is implicitly modeled via additional external constraints between the residues in contact with the surface. We first performed calculations on a redox enzyme, bilirubin oxidase (BOD) from M. verrucaria, to study the impact of adsorption on its mechanical properties. The resulting rigidity profiles show that, in agreement with the available experimental data, the mechanical variations observed in the adsorbed BOD will depend on its orientation and its anchor residues (i.e., residues that are in contact with the functionalized surface). Additional calculations on ribonuclease A and nitroreductase shed light on how seemingly stable adsorbed enzymes can nonetheless display an important decrease in their catalytic activity resulting from a perturbation of their mechanics and internal dynamics.
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Affiliation(s)
- Nicolas Bourassin
- CNRS, Laboratoire de Biochimie Théorique, UPR 9080, Université de Paris, 13 rue Pierre et Marie Curie, 75005 Paris, France.,Institut de Biologie Physico-Chimique-Fondation Edmond de Rotschild, PSL Research University, 75006 Paris, France
| | - Marc Baaden
- CNRS, Laboratoire de Biochimie Théorique, UPR 9080, Université de Paris, 13 rue Pierre et Marie Curie, 75005 Paris, France.,Institut de Biologie Physico-Chimique-Fondation Edmond de Rotschild, PSL Research University, 75006 Paris, France
| | - Elisabeth Lojou
- CNRS, Bioénergétique et Ingénierie des Protéines, UMR 7281, Aix Marseille Univ, 31, chemin Joseph Aiguier, CS 70071, 13402 Cedex 09 Marseille, France
| | - Sophie Sacquin-Mora
- CNRS, Laboratoire de Biochimie Théorique, UPR 9080, Université de Paris, 13 rue Pierre et Marie Curie, 75005 Paris, France.,Institut de Biologie Physico-Chimique-Fondation Edmond de Rotschild, PSL Research University, 75006 Paris, France
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46
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Liu S, Ban X, Zeng X, Zhao F, Gao Y, Wu W, Zhang H, Chen F, Hall T, Gao X, Xu M. A unified framework for packing deformable and non-deformable subcellular structures in crowded cryo-electron tomogram simulation. BMC Bioinformatics 2020; 21:399. [PMID: 32907544 PMCID: PMC7488303 DOI: 10.1186/s12859-020-03660-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 07/14/2020] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Cryo-electron tomography is an important and powerful technique to explore the structure, abundance, and location of ultrastructure in a near-native state. It contains detailed information of all macromolecular complexes in a sample cell. However, due to the compact and crowded status, the missing edge effect, and low signal to noise ratio (SNR), it is extremely challenging to recover such information with existing image processing methods. Cryo-electron tomogram simulation is an effective solution to test and optimize the performance of the above image processing methods. The simulated images could be regarded as the labeled data which covers a wide range of macromolecular complexes and ultrastructure. To approximate the crowded cellular environment, it is very important to pack these heterogeneous structures as tightly as possible. Besides, simulating non-deformable and deformable components under a unified framework also need to be achieved. RESULT In this paper, we proposed a unified framework for simulating crowded cryo-electron tomogram images including non-deformable macromolecular complexes and deformable ultrastructures. A macromolecule was approximated using multiple balls with fixed relative positions to reduce the vacuum volume. A ultrastructure, such as membrane and filament, was approximated using multiple balls with flexible relative positions so that this structure could deform under force field. In the experiment, 400 macromolecules of 20 representative types were packed into simulated cytoplasm by our framework, and numerical verification proved that our method has a smaller volume and higher compression ratio than the baseline single-ball model. We also packed filaments, membranes and macromolecules together, to obtain a simulated cryo-electron tomogram image with deformable structures. The simulated results are closer to the real Cryo-ET, making the analysis more difficult. The DOG particle picking method and the image segmentation method are tested on our simulation data, and the experimental results show that these methods still have much room for improvement. CONCLUSION The proposed multi-ball model can achieve more crowded packaging results and contains richer elements with different properties to obtain more realistic cryo-electron tomogram simulation. This enables users to simulate cryo-electron tomogram images with non-deformable macromolecular complexes and deformable ultrastructures under a unified framework. To illustrate the advantages of our framework in improving the compression ratio, we calculated the volume of simulated macromolecular under our multi-ball method and traditional single-ball method. We also performed the packing experiment of filaments and membranes to demonstrate the simulation ability of deformable structures. Our method can be used to do a benchmark by generating large labeled cryo-ET dataset and evaluating existing image processing methods. Since the content of the simulated cryo-ET is more complex and crowded compared with previous ones, it will pose a greater challenge to existing image processing methods.
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Affiliation(s)
- Sinuo Liu
- Beijing Advanced Innovation Center for Materials Genome Engineering, School of Computer and Communication Engineering, University of Science and Technology Beijing, Beijing, China
- Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA United States
| | - Xiaojuan Ban
- Beijing Advanced Innovation Center for Materials Genome Engineering, School of Computer and Communication Engineering, University of Science and Technology Beijing, Beijing, China
| | - Xiangrui Zeng
- Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA United States
| | - Fengnian Zhao
- WuYuzhang Honors College, Sichuan University, Sichuan, China
| | - Yuan Gao
- Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA United States
| | | | - Hongpan Zhang
- School of Information Science and Technology, Beijing Forestry University, Beijing, China
- College of Life Science, Sichuan University, Sichuan, China
| | - Feiyang Chen
- Thuwal, Saudi Arabia, King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division, Thuwal, Saudi Arabia
| | - Thomas Hall
- Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA United States
| | - Xin Gao
- School of Mechanical, Electrical and Information Engineering, Shandong University, Shandong, China
| | - Min Xu
- Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA United States
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47
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Ramasubramani V, Vo T, Anderson JA, Glotzer SC. A mean-field approach to simulating anisotropic particles. J Chem Phys 2020; 153:084106. [DOI: 10.1063/5.0019735] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Affiliation(s)
- Vyas Ramasubramani
- Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan 48109, USA
| | - Thi Vo
- Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan 48109, USA
| | - Joshua A. Anderson
- Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan 48109, USA
| | - Sharon C. Glotzer
- Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan 48109, USA
- Department of Materials Science and Engineering, University of Michigan, Ann Arbor, Michigan 48109, USA
- Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan 48109, USA
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48
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Badu S, Melnik R, Singh S. Mathematical and computational models of RNA nanoclusters and their applications in data-driven environments. MOLECULAR SIMULATION 2020. [DOI: 10.1080/08927022.2020.1804564] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Shyam Badu
- MS2Discovery Interdisciplinary Research Institute, Wilfrid Laurier University, Waterloo, Ontario, Canada
| | - Roderick Melnik
- MS2Discovery Interdisciplinary Research Institute, Wilfrid Laurier University, Waterloo, Ontario, Canada
- BCAM-Basque Center for Applied Mathematics, Bilbao, Spain
| | - Sundeep Singh
- MS2Discovery Interdisciplinary Research Institute, Wilfrid Laurier University, Waterloo, Ontario, Canada
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49
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Baul U, Bley M, Dzubiella J. Thermal Compaction of Disordered and Elastin-like Polypeptides: A Temperature-Dependent, Sequence-Specific Coarse-Grained Simulation Model. Biomacromolecules 2020; 21:3523-3538. [DOI: 10.1021/acs.biomac.0c00546] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Upayan Baul
- Applied Theoretical Physics—Computational Physics, Physikalisches Institut, Albert-Ludwigs-Universität Freiburg, Hermann-Herder Strasse 3, D-79104 Freiburg, Germany
| | - Michael Bley
- Applied Theoretical Physics—Computational Physics, Physikalisches Institut, Albert-Ludwigs-Universität Freiburg, Hermann-Herder Strasse 3, D-79104 Freiburg, Germany
| | - Joachim Dzubiella
- Applied Theoretical Physics—Computational Physics, Physikalisches Institut, Albert-Ludwigs-Universität Freiburg, Hermann-Herder Strasse 3, D-79104 Freiburg, Germany
- Cluster of Excellence livMatS@FIT—Freiburg Center for Interactive Materials and Bioinspired Technologies, Albert-Ludwigs-Universität Freiburg, Georges-Köhler-Allee 105, D-79110 Freiburg, Germany
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50
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Shao Q, Gong W, Li C. A study on allosteric communication in U1A-snRNA binding interactions: network analysis combined with molecular dynamics data. Biophys Chem 2020; 264:106393. [PMID: 32653695 DOI: 10.1016/j.bpc.2020.106393] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 05/02/2020] [Accepted: 05/03/2020] [Indexed: 01/09/2023]
Abstract
The allosteric regulation during the binding interactions between small nuclear RNAs (snRNAs) and the associated protein factors is critical to the function of spliceosomes in alternative RNA splicing. Although network models combined with molecular dynamics simulations have shown to be powerful tools for the analysis of protein allostery, the atomic-level simulations are, however, too expensive and with limited accuracy for the large-size systems. In this work, we use a residual network model combined with a coarse-grained Gaussian network model (GNM) to investigate the binding interactions between the snRNA and the human U1A protein which is a major component of the spliceosomal U1 small nuclear ribonucleoprotein particle, and to identify the residues that play an important role in the allosteric communication in U1A during this process. We also utilize the Girvan-Newman method to detect the structural organization in U1A-snRNA recognition and interactions. Our results reveal that: (Ι) not only the residues at the binding sites that are traditionally considered to play a major role in U1A-snRNA association, but those residues that are far away from the RNA binding interface participate in the U1A's allosteric signal transmission induced by the RNA binding; (Π) the structure of U1A protein is well organized with different communities acting different roles for its RNA binding and allosteric regulation. The study demonstrates that the combination of the residual network and elastic network models is an effective and efficient method which can be readily extended to the investigation of the allosteric communication for other macromolecular interaction systems.
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Affiliation(s)
- Qi Shao
- College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, China
| | - Weikang Gong
- College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, China
| | - Chunhua Li
- College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, China.
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