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

Ivan Teo, Christopher G. Mayne, Klaus J Schulten, Tony Lelièvre

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article number065114
Pages (from-to)2983-2989
Number of pages7
JournalJournal of Chemical Theory and Computation
Volume12
Issue number6
DOIs
StatePublished - Jun 14 2016

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ASJC Scopus subject areas

  • Computer Science Applications
  • Physical and Theoretical Chemistry

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