Efficient calculation of relative binding free energies by umbrella sampling perturbation
© 2014 Wiley Periodicals, Inc.
| Publié dans: | Journal of computational chemistry. - 1984. - 35(2014), 31 vom: 05. Dez., Seite 2256-62 |
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| Auteur principal: | |
| Autres auteurs: | |
| Format: | Article en ligne |
| Langue: | English |
| Publié: |
2014
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| Accès à la collection: | Journal of computational chemistry |
| Sujets: | Journal Article Research Support, Non-U.S. Gov't alanine scan drug design free energy perturbation ligand-receptor binding molecular dynamics simulation potential of mean force Peptides Alanine |
| Résumé: | © 2014 Wiley Periodicals, Inc. An important task of biomolecular simulation is the calculation of relative binding free energies upon chemical modification of partner molecules in a biomolecular complex. The potential of mean force (PMF) along a reaction coordinate for association or dissociation of the complex can be used to estimate binding affinities. A free energy perturbation approach, termed umbrella sampling (US) perturbation, has been designed that allows an efficient calculation of the change of the PMF upon modification of a binding partner based on the trajectories obtained for the wild type reference complex. The approach was tested on the interaction of modified water molecules in aqueous solution and applied to in silico alanine scanning of a peptide-protein complex. For the water interaction test case, excellent agreement with an explicit PMF calculation for each modification was obtained as long as no long range electrostatic perturbations were considered. For the alanine scanning, the experimentally determined ranking and binding affinity changes upon alanine substitutions could be reproduced within 0.1-2.0 kcal/mol. In addition, good agreement with explicitly calculated PMFs was obtained mostly within the sampling uncertainty. The combined US and perturbation approach yields, under the condition of sufficiently small system modifications, rigorously derived changes in free energy and is applicable to any PMF calculation |
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| Description: | Date Completed 22.06.2015 Date Revised 27.10.2014 published: Print-Electronic Citation Status MEDLINE |
| ISSN: | 1096-987X |
| DOI: | 10.1002/jcc.23744 |