title: Adaptive Multilevel Splitting Method for Molecular Dynamics Calculation of Benzamidine-Trypsin Dissociation Time.
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) × 10(2) s(-1), which compares well with the experimental value.
authors.affiliation: Beckman Institute for Advanced Science and Technology , 405 North Mathews Avenue, Urbana, Illinois, 61801 United States.|Department of Physics, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.
authors.forename: Ivan
authors.initials: I
authors.lastname: Teo
authors.affiliation: Beckman Institute for Advanced Science and Technology , 405 North Mathews Avenue, Urbana, Illinois, 61801 United States.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Mayne
authors.affiliation: Beckman Institute for Advanced Science and Technology , 405 North Mathews Avenue, Urbana, Illinois, 61801 United States.|Department of Physics, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulten
authors.affiliation: CERMICS, École des Ponts ParisTech, 6-8 Avenue Blaise Pascal, 77455 Marne La Vallée, France.
authors.forename: Tony
authors.initials: T
authors.lastname: Lelièvre
mesh_terms: D000465:Algorithms; D001550:Benzamidines / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D056004:Molecular Dynamics Simulation; D009010:Monte Carlo Method; D011485:Protein Binding; D014357:Trypsin / Q000737:chemistry* / Q000378:metabolism
chemical_list: D001550:Benzamidines; D008024:Ligands; D014357:Trypsin