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Sampling Conformational Changes of Bound Ligands Using Nonequilibrium Candidate Monte Carlo and Molecular Dynamics
journal contribution
posted on 2020-02-24, 19:03 authored by Sukanya Sasmal, Samuel C. Gill, Nathan M. Lim, David L. MobleyFlexible
ligands often have multiple binding modes or bound conformations
that differ by rotation of a portion of the molecule around internal
rotatable bonds. Knowledge of these binding modes is important for
understanding the interactions stabilizing the ligand in the binding
pocket, and other studies indicate it is important for calculating
accurate binding affinities. In this work, we use a hybrid molecular
dynamics (MD)/nonequilibrium candidate Monte Carlo (NCMC) method to
sample the different binding modes of several flexible ligands and
also to estimate the population distribution of the modes. The NCMC
move proposal is divided into three parts. The flexible part of the
ligand is alchemically turned off by decreasing the electrostatics
and steric interactions gradually, followed by rotating the rotatable
bond by a random angle and then slowly turning the ligand back on
to its fully interacting state. The alchemical steps prior to and
after the move proposal help the surrounding protein and water atoms
in the binding pocket relax around the proposed ligand conformation
and increase move acceptance rates. The protein–ligand system
is propagated using classical MD in between the NCMC proposals. Using
this MD/NCMC method, we were able to correctly reproduce the different
binding modes of inhibitors binding to two kinase targetsc-Jun
N-terminal kinase-1 and cyclin-dependent kinase 2at a much
lower computational cost compared to conventional MD and umbrella
sampling. This method is available as a part of the BLUES software
package.