scholarly journals The Automated Optimisation of a Coarse-Grained Force Field Using Free Energy Data

2021 ◽  
Author(s):  
Javier Caceres-Delpiano ◽  
Lee-Ping Wang ◽  
Jonathan Wynne Essex
Keyword(s):  
Free Energy ◽  
Force Field ◽  
Coarse Grained ◽  
Energy Data ◽  
Molecular Systems ◽  
Atomistic Models ◽  
Large Systems ◽  
Long Timescales

Atomistic models provide a detailed representation of molecular systems, but are sometimes inadequate for simulations of large systems over long timescales. Coarse-grained models enable accelerated simulations by reducing the number...

scholarly journals The Automated Optimisation of a Coarse-Grained Force Field Using Free Energy Data

2020 ◽  
Author(s):  
Javier Caceres-Delpiano ◽  
Lee-Ping Wang ◽  
Jonathan W. Essex
Keyword(s):  
Free Energy ◽  
Force Field ◽  
Degrees Of Freedom ◽  
Coarse Grained ◽  
Free Energies ◽  
Energy Data ◽  
Molecular Systems ◽  
Atomistic Models ◽  
The Cost ◽  
Long Timescales

AbstractAtomistic models provide a detailed representation of molecular systems, but are sometimes inadequate for simulations of large systems over long timescales. Coarse-grained models enable accelerated simulations by reducing the number of degrees of freedom, at the cost of reduced accuracy. New optimisation processes to parameterise these models could improve their quality and range of applicability. We present an automated approach for the optimisation of coarse-grained force fields, by reproducing free energy data derived from atomistic molecular simulations. To illustrate the approach, we implemented hydration free energy gradients as a new target for force field optimisation in ForceBalance and applied it successfully to optimise the un-charged side-chains and the protein backbone in the SIRAH protein coarse-grain force field. The optimised parameters closely reproduced hydration free energies of atomistic models and gave improved agreement with experiment.

scholarly journals Evaluating the Efficiency of the Martini Force Field to Study Protein Dimerization in Aqueous and Membrane Environments

2021 ◽  
Author(s):  
Christos Lamprakis ◽  
Ioannis Andreadelis ◽  
John Manchester ◽  
Camilo Velez-Vega ◽  
José S. Duca ◽  
...  
Keyword(s):  
Free Energy ◽  
Membrane Proteins ◽  
Force Field ◽  
Biological Activities ◽  
Coarse Grained ◽  
Protein Oligomerization ◽  
Free Energy Surface ◽  
Collective Variables ◽  
Protein Dimerization ◽  
Dimerization Process

<p>Protein-protein complex assembly is one of the major drivers of biological response. Understanding the mechanisms of protein oligomerization/dimerization would allow one to elucidate how these complexes participate in biological activities and could ultimately lead to new approaches in designing novel therapeutic agents. However, determining the exact association pathways and structures of such complexes remains a challenge. Here, we use parallel tempering metadynamics simulations in the well-tempered ensemble to evaluate the performance of Martini 2.2P and Martini open-beta 3 (Martini 3) force fields in reproducing the structure and energetics of the dimerization process of membrane proteins and proteins in an aqueous solution in reasonable accuracy and throughput. We find that Martini 2.2P systematically overestimates the free energy of association by estimating large barriers in distinct areas, which likely leads to overaggregation when multiple monomers are present. In comparison, the less viscous Martini 3 results in a systematic underestimation of the free energy of association for proteins in solution, while it performs well in describing the association of membrane proteins. In all cases the near-native dimer complexes are identified as minima in the free energy surface albeit not always as the lowest minima. In the case of Martini 3 we find that the spurious supramolecular protein aggregation present in Martini 2.2P multimer simulations is alleviated and thus this force field may be more suitable for the study of protein oligomerization. We propose that the use of enhanced sampling simulations with a refined coarse-grained force field and appropriately defined collective variables is a robust approach for studying the protein dimerization process, although one should be cautious of the ranking of energy minima.</p>

scholarly journals Evaluating the Efficiency of the Martini Force Field to Study Protein Dimerization in Aqueous and Membrane Environments

2021 ◽  
Author(s):  
Christos Lamprakis ◽  
Ioannis Andreadelis ◽  
John Manchester ◽  
Camilo Velez-Vega ◽  
José S. Duca ◽  
...  
Keyword(s):  
Free Energy ◽  
Membrane Proteins ◽  
Force Field ◽  
Biological Activities ◽  
Coarse Grained ◽  
Protein Oligomerization ◽  
Free Energy Surface ◽  
Collective Variables ◽  
Protein Dimerization ◽  
Dimerization Process

<p>Protein-protein complex assembly is one of the major drivers of biological response. Understanding the mechanisms of protein oligomerization/dimerization would allow one to elucidate how these complexes participate in biological activities and could ultimately lead to new approaches in designing novel therapeutic agents. However, determining the exact association pathways and structures of such complexes remains a challenge. Here, we use parallel tempering metadynamics simulations in the well-tempered ensemble to evaluate the performance of Martini 2.2P and Martini open-beta 3 (Martini 3) force fields in reproducing the structure and energetics of the dimerization process of membrane proteins and proteins in an aqueous solution in reasonable accuracy and throughput. We find that Martini 2.2P systematically overestimates the free energy of association by estimating large barriers in distinct areas, which likely leads to overaggregation when multiple monomers are present. In comparison, the less viscous Martini 3 results in a systematic underestimation of the free energy of association for proteins in solution, while it performs well in describing the association of membrane proteins. In all cases the near-native dimer complexes are identified as minima in the free energy surface albeit not always as the lowest minima. In the case of Martini 3 we find that the spurious supramolecular protein aggregation present in Martini 2.2P multimer simulations is alleviated and thus this force field may be more suitable for the study of protein oligomerization. We propose that the use of enhanced sampling simulations with a refined coarse-grained force field and appropriately defined collective variables is a robust approach for studying the protein dimerization process, although one should be cautious of the ranking of energy minima.</p>

scholarly journals Lipids in the Piezo1 channel pore: gating mechanism, or simulation artifact?

2021 ◽  
Author(s):  
Wenjuan Jiang ◽  
Jerome Jacques Lacroix ◽  
Yun Luo
Keyword(s):  
Free Energy ◽  
Force Field ◽  
Binding Free Energy ◽  
Simulated Data ◽  
Free Energy Calculations ◽  
Coarse Grained ◽  
Computational Simulations ◽  
Gating Mechanism ◽  
Reverse Mapping ◽  
Absolute Binding Free Energy

Opening and closure of certain mechanosensitive ion channels have recently been linked with the presence of lipids in or near their pores. Although non-conducting structures of mechanosensitive Piezo channels do not show the presence of lipids in the pore, computational simulations suggest whole phospholipids enter the Piezo1 pore in the closed state. Here, to probe this phenomenon, we conduct coarse-grained (CG) and all-atom (AA) simulations of Piezo1 with different solvation algorithms and equilibrium protocols, including CG-to-AA reverse mapping from Martini CG force field to CHARMM AA force field. Our results show that the lack of initial hydration of the upper pore region, enabled by common CG but not AA solvation algorithms, allows entry of whole lipids through gaps between pore helices during subsequent equilibrium simulations. Absolute binding free energy calculations show that these lipids are thermodynamically unfavorable, indicating they are likely kinetically trapped in the pore during microsecond-long AA simulations. An alternative equilibrium protocol is proposed to avoid such simulation artifact for channels whose pores are walled with transmembrane gaps. This work underscores the notion that, as simulated systems become increasingly complex, interpretation of simulated data in physiological contexts requires extra precautions. When no experimental data is available, free energy approaches such as those implemented here appear as trustworthy validations of results observed from MD trajectories.

Hydration Free Energies of Organic Molecules in the FreeSolv Database Calculated with Polarized Atom In Molecules Atomic Charges and the GAFF Force Field.

2018 ◽  
Author(s):  
Maximiliano Riquelme ◽  
Alejandro Lara ◽  
David L. Mobley ◽  
Toon Vestraelen ◽  
Adelio R Matamala ◽  
...  
Keyword(s):  
Force Field ◽  
Functional Groups ◽  
Electrostatic Interactions ◽  
Organic Molecules ◽  
Force Fields ◽  
Chemical Elements ◽  
Atomic Charges ◽  
Free Energies ◽  
Molecular Systems ◽  
Solvent Model

<div>Computer simulations of bio-molecular systems often use force fields, which are combinations of simple empirical atom-based functions to describe the molecular interactions. Even though polarizable force fields give a more detailed description of intermolecular interactions, nonpolarizable force fields, developed several decades ago, are often still preferred because of their reduced computation cost. Electrostatic interactions play a major role in bio-molecular systems and are therein described by atomic point charges.</div><div>In this work, we address the performance of different atomic charges to reproduce experimental hydration free energies in the FreeSolv database in combination with the GAFF force field. Atomic charges were calculated by two atoms-in-molecules approaches, Hirshfeld-I and Minimal Basis Iterative Stockholder (MBIS). To account for polarization effects, the charges were derived from the solute's electron density computed with an implicit solvent model and the energy required to polarize the solute was added to the free energy cycle. The calculated hydration free energies were analyzed with an error model, revealing systematic errors associated with specific functional groups or chemical elements. The best agreement with the experimental data is observed for the MBIS atomic charge method, including the solvent polarization, with a root mean square error of 2.0 kcal mol<sup>-1</sup> for the 613 organic molecules studied. The largest deviation was observed for phosphor-containing molecules and the molecules with amide, ester and amine functional groups.</div>

scholarly journals How proteins open fusion pores: insights from molecular simulations

2020 ◽  
Author(s):  
H. Jelger Risselada ◽  
Helmut Grubmüller
Keyword(s):  
Free Energy ◽  
Fusion Proteins ◽  
Graphics Processing Units ◽  
Fusion Reaction ◽  
Molecular Simulations ◽  
Minimum Free Energy ◽  
Free Energy Calculations ◽  
Coarse Grained ◽  
Fusion Pore ◽  
Graphics Processing

AbstractFusion proteins can play a versatile and involved role during all stages of the fusion reaction. Their roles go far beyond forcing the opposing membranes into close proximity to drive stalk formation and fusion. Molecular simulations have played a central role in providing a molecular understanding of how fusion proteins actively overcome the free energy barriers of the fusion reaction up to the expansion of the fusion pore. Unexpectedly, molecular simulations have revealed a preference of the biological fusion reaction to proceed through asymmetric pathways resulting in the formation of, e.g., a stalk-hole complex, rim-pore, or vertex pore. Force-field based molecular simulations are now able to directly resolve the minimum free-energy path in protein-mediated fusion as well as quantifying the free energies of formed reaction intermediates. Ongoing developments in Graphics Processing Units (GPUs), free energy calculations, and coarse-grained force-fields will soon gain additional insights into the diverse roles of fusion proteins.

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