TY - JOUR
T1 - Adaptive Multilevel Splitting Method for Molecular Dynamics Calculation of Benzamidine-Trypsin Dissociation Time
AU - Teo, Ivan
AU - Mayne, Christopher G.
AU - Schulten, Klaus
AU - Lelièvre, Tony
N1 - Publisher Copyright:
© 2016 American Chemical Society.
PY - 2016/6/14
Y1 - 2016/6/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84975082620&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84975082620&partnerID=8YFLogxK
U2 - 10.1021/acs.jctc.6b00277
DO - 10.1021/acs.jctc.6b00277
M3 - Article
C2 - 27159059
AN - SCOPUS:84975082620
SN - 1549-9618
VL - 12
SP - 2983
EP - 2989
JO - Journal of Chemical Theory and Computation
JF - Journal of Chemical Theory and Computation
IS - 6
M1 - 065114
ER -