Open AccessReversibly Sampling Conformations and Binding Modes Using Molecular Darting
Author(s) -
Samuel C. Gill,
David L. Mobley
Publication year - 2020
Publication title -
journal of chemical theory and computation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.001
H-Index - 185
eISSN - 1549-9626
pISSN - 1549-9618
DOI - 10.1021/acs.jctc.0c00752
Subject(s) - monte carlo method , ligand (biochemistry) , molecular dynamics , sampling (signal processing) , degrees of freedom (physics and chemistry) , statistical physics , chemistry , physics , computational chemistry , mathematics , thermodynamics , statistics , biochemistry , receptor , detector , optics
Sampling multiple binding modes of a ligand in a single molecular dynamics simulation is difficult. A given ligand may have many internal degrees of freedom, along with many different ways it might orient itself in a binding site or across several binding sites, all of which might be separated by large energy barriers. We have developed a novel Monte Carlo move called molecular darting (MolDarting) to reversibly sample between predefined binding modes of a ligand. Here, we couple this with nonequilibrium candidate Monte Carlo (NCMC) to improve acceptance of moves. We apply this technique to a simple dipeptide system, a ligand binding to T4 lysozyme L99A, and ligand binding to HIV integrase to test this new method. We observe significant increases in acceptance compared to uniformly sampling the internal and rotational/translational degrees of freedom in these systems.