These are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information. For more information, please see our FAQs.
BLUES_dihedrals.pdf (3.74 MB)

Sampling Conformational Changes of Bound Ligands Using Nonequilibrium Candidate Monte Carlo

submitted on 18.10.2019, 17:25 and posted on 23.10.2019, 15:20 by Sukanya Sasmal, Samuel C. Gill, Nathan M. Lim, David Mobley
Flexible 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 also for calculating accurate binding affinities. In this work, we use a hybrid molecular dynamics (MD)/non-equilibrium 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 targets -- c-Jun N-terminal kinase-1 and cyclin-dependent kinase 2 -- at a much lower computational cost compared to conventional MD and umbrella sampling. This method is available as a part of the BLUES software package.


NIGMS R01GM108889

NIGMS 1R01GM124270-01A1


Email Address of Submitting Author


University of California, Irvine


United States

ORCID For Submitting Author


Declaration of Conflict of Interest

David Mobley serves on the scientific advisory board of OpenEye Scientific Software and is an Open Science Fellow with Silicon Therapeutics.