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Adaptive Multilevel Splitting Method for Molecular Dynamics Calculation of Benzamidine-Trypsin Dissociation Time

Authors :
Christopher G. Mayne
Tony Lelièvre
Ivan Teo
Klaus Schulten
Department of Physics [Illinois at Urbana-Champaign, USA]
University of Illinois at Urbana-Champaign [Urbana]
University of Illinois System-University of Illinois System
The Beckman Institute for Advanced Science and Technology
Centre d'Enseignement et de Recherche en Mathématiques et Calcul Scientifique (CERMICS)
École des Ponts ParisTech (ENPC)
MATHematics for MatERIALS (MATHERIALS)
École des Ponts ParisTech (ENPC)-École des Ponts ParisTech (ENPC)-Inria de Paris
Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)
European Project: 614492,EC:FP7:ERC,ERC-2013-CoG,MSMATH(2014)
Inria de Paris
Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre d'Enseignement et de Recherche en Mathématiques et Calcul Scientifique (CERMICS)
École des Ponts ParisTech (ENPC)-École des Ponts ParisTech (ENPC)
Source :
Journal of Chemical Theory and Computation, Journal of Chemical Theory and Computation, 2016, 12 (6), pp.2983-2989. ⟨10.1021/acs.jctc.6b00277⟩, Journal of Chemical Theory and Computation, American Chemical Society, 2016, 12 (6), pp.2983-2989. ⟨10.1021/acs.jctc.6b00277⟩
Publication Year :
2016
Publisher :
HAL CCSD, 2016.

Abstract

International audience Adaptive multilevel splitting (AMS) is a rare event sampling method that requires minimal parameter tuning and allows unbiased sampling of transition pathways of a given rare event. Previous simulation studies have verified the efficiency and accuracy of AMS in the calculation of transition times for simple systems in both Monte Carlo and molecular dynamics (MD) simulations. Now, AMS is applied for the first time to an MD simulation of protein–ligand dissociation, representing a leap in complexity from the previous test cases. Of interest is the dissociation rate, which is typically too low to be accessible to conventional MD. The present study joins other recent efforts to develop advanced sampling techniques in MD to calculate dissociation rates, which are gaining importance in the pharmaceutical field as indicators of drug efficacy. The system investigated here, benzamidine bound to trypsin, is an example common to many of these efforts. The AMS estimate of the dissociation rate was found to be (2.6 ± 2.4) × 102 s–1, which compares well with the experimental value.

Details

Language :
English
ISSN :
15499618 and 15499626
Database :
OpenAIRE
Journal :
Journal of Chemical Theory and Computation, Journal of Chemical Theory and Computation, 2016, 12 (6), pp.2983-2989. ⟨10.1021/acs.jctc.6b00277⟩, Journal of Chemical Theory and Computation, American Chemical Society, 2016, 12 (6), pp.2983-2989. ⟨10.1021/acs.jctc.6b00277⟩
Accession number :
edsair.doi.dedup.....619df35739b846654972221710afd9dd
Full Text :
https://doi.org/10.1021/acs.jctc.6b00277⟩