Reversibly Sampling Conformations and Binding Modes Using Molecular Darting

20 July 2020, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

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 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 in order 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.

Keywords

ligand binding
nonequilibrium candidate Monte Carlo
NCMC
molecular dynamics
BLUES

Supplementary materials

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