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Using Selectively Applied Accelerated Molecular Dynamics to Enhance Free Energy Calculations
Accelerated molecular dynamics (aMD) has been shown to enhance conformational space sampling relative to classical molecular dynamics; however, the exponential reweighting of aMD trajectories, which is necessary for the calculation of free energies relating to the classical system, is oftentimes pro...
Autores principales: | , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2010
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2976571/ https://www.ncbi.nlm.nih.gov/pubmed/21072329 http://dx.doi.org/10.1021/ct100322t |
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author | Wereszczynski, Jeff McCammon, J. Andrew |
author_facet | Wereszczynski, Jeff McCammon, J. Andrew |
author_sort | Wereszczynski, Jeff |
collection | PubMed |
description | Accelerated molecular dynamics (aMD) has been shown to enhance conformational space sampling relative to classical molecular dynamics; however, the exponential reweighting of aMD trajectories, which is necessary for the calculation of free energies relating to the classical system, is oftentimes problematic, especially for systems larger than small poly peptides. Here, we propose a method of accelerating only the degrees of freedom most pertinent to sampling, thereby reducing the total acceleration added to the system and improving the convergence of calculated ensemble averages, which we term selective aMD. Its application is highlighted in two biomolecular cases. First, the model system alanine dipeptide is simulated with classical MD, all-dihedral aMD, and selective aMD, and these results are compared to the infinite sampling limit as calculated with metadynamics. We show that both forms of aMD enhance the convergence of the underlying free energy landscape by 5-fold relative to classical MD; however, selective aMD can produce improved statistics over all-dihedral aMD due to the improved reweighting. Then we focus on the pharmaceutically relevant case of computing the free energy of the decoupling of oseltamivir in the active site of neuraminidase. Results show that selective aMD greatly reduces the cost of this alchemical free energy transformation, whereas all-dihedral aMD produces unreliable free energy estimates. |
format | Text |
id | pubmed-2976571 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-29765712010-11-09 Using Selectively Applied Accelerated Molecular Dynamics to Enhance Free Energy Calculations Wereszczynski, Jeff McCammon, J. Andrew J Chem Theory Comput Accelerated molecular dynamics (aMD) has been shown to enhance conformational space sampling relative to classical molecular dynamics; however, the exponential reweighting of aMD trajectories, which is necessary for the calculation of free energies relating to the classical system, is oftentimes problematic, especially for systems larger than small poly peptides. Here, we propose a method of accelerating only the degrees of freedom most pertinent to sampling, thereby reducing the total acceleration added to the system and improving the convergence of calculated ensemble averages, which we term selective aMD. Its application is highlighted in two biomolecular cases. First, the model system alanine dipeptide is simulated with classical MD, all-dihedral aMD, and selective aMD, and these results are compared to the infinite sampling limit as calculated with metadynamics. We show that both forms of aMD enhance the convergence of the underlying free energy landscape by 5-fold relative to classical MD; however, selective aMD can produce improved statistics over all-dihedral aMD due to the improved reweighting. Then we focus on the pharmaceutically relevant case of computing the free energy of the decoupling of oseltamivir in the active site of neuraminidase. Results show that selective aMD greatly reduces the cost of this alchemical free energy transformation, whereas all-dihedral aMD produces unreliable free energy estimates. American Chemical Society 2010-10-13 2010-11-09 /pmc/articles/PMC2976571/ /pubmed/21072329 http://dx.doi.org/10.1021/ct100322t Text en Copyright © 2010 American Chemical Society http://pubs.acs.org This is an open-access article distributed under the ACS AuthorChoice Terms & Conditions. Any use of this article, must conform to the terms of that license which are available at http://pubs.acs.org. |
spellingShingle | Wereszczynski, Jeff McCammon, J. Andrew Using Selectively Applied Accelerated Molecular Dynamics to Enhance Free Energy Calculations |
title | Using Selectively Applied Accelerated Molecular Dynamics to Enhance Free Energy Calculations |
title_full | Using Selectively Applied Accelerated Molecular Dynamics to Enhance Free Energy Calculations |
title_fullStr | Using Selectively Applied Accelerated Molecular Dynamics to Enhance Free Energy Calculations |
title_full_unstemmed | Using Selectively Applied Accelerated Molecular Dynamics to Enhance Free Energy Calculations |
title_short | Using Selectively Applied Accelerated Molecular Dynamics to Enhance Free Energy Calculations |
title_sort | using selectively applied accelerated molecular dynamics to enhance free energy calculations |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2976571/ https://www.ncbi.nlm.nih.gov/pubmed/21072329 http://dx.doi.org/10.1021/ct100322t |
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