Accelerating Rare Dissociative Processes in Biomolecules Using Selectively Scaled MD Simulations

TY - JOUR

T1 - Accelerating Rare Dissociative Processes in Biomolecules Using Selectively Scaled MD Simulations

AU - Deb, Indrajit

AU - Frank, Aaron T.

N1 - Publisher Copyright: Copyright © 2019 American Chemical Society.

PY - 2019/11/12

Y1 - 2019/11/12

N2 - Molecular dynamics (MD) simulations can be a powerful tool for modeling complex dissociative processes such as ligand unbinding. However, many biologically relevant dissociative processes occur on timescales that far exceed the timescales of typical MD simulations. Here, we implement and apply an enhanced sampling method in which specific energy terms in the potential energy function are selectively "scaled" to accelerate dissociative events during simulations. Using ligand unbinding as an example of a complex dissociative process, we selectively scaled up ligand-water interactions in an attempt to increase the rate of ligand unbinding. After applying our selectively scaled MD (ssMD) approach to several cyclin-dependent kinase-inhibitor complexes, we discovered that we could accelerate ligand unbinding, thereby allowing, in some cases, unbinding events to occur within as little as 2 ns. Moreover, we found that we could make realistic estimates of the initial unbinding times (τunbindsim) as well as the accompanying change in free energy (ΔGsim) of the inhibitors from our ssMD simulation data. To accomplish this, we employed a previously described Kramers'-based rate extrapolation method and a newly described free energy extrapolation method. Because our ssMD approach is general, it should find utility as an easy-to-deploy, enhanced sampling method for modeling other dissociative processes.

AB - Molecular dynamics (MD) simulations can be a powerful tool for modeling complex dissociative processes such as ligand unbinding. However, many biologically relevant dissociative processes occur on timescales that far exceed the timescales of typical MD simulations. Here, we implement and apply an enhanced sampling method in which specific energy terms in the potential energy function are selectively "scaled" to accelerate dissociative events during simulations. Using ligand unbinding as an example of a complex dissociative process, we selectively scaled up ligand-water interactions in an attempt to increase the rate of ligand unbinding. After applying our selectively scaled MD (ssMD) approach to several cyclin-dependent kinase-inhibitor complexes, we discovered that we could accelerate ligand unbinding, thereby allowing, in some cases, unbinding events to occur within as little as 2 ns. Moreover, we found that we could make realistic estimates of the initial unbinding times (τunbindsim) as well as the accompanying change in free energy (ΔGsim) of the inhibitors from our ssMD simulation data. To accomplish this, we employed a previously described Kramers'-based rate extrapolation method and a newly described free energy extrapolation method. Because our ssMD approach is general, it should find utility as an easy-to-deploy, enhanced sampling method for modeling other dissociative processes.

UR - https://www.scopus.com/pages/publications/85073799298

U2 - 10.1021/acs.jctc.9b00262

DO - 10.1021/acs.jctc.9b00262

M3 - Article

C2 - 31509413

AN - SCOPUS:85073799298

SN - 1549-9618

VL - 15

SP - 5817

EP - 5828

JO - Journal of Chemical Theory and Computation

JF - Journal of Chemical Theory and Computation

IS - 11

ER -