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Reversibly Sampling Conformations and Binding Modes Using Molecular Darting

revised on 26.10.2020, 18:43 and posted on 28.10.2020, 08:15 by Samuel C. Gill, David Mobley
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.


Computational alchemy for molecular design and optimization

National Institute of General Medical Sciences

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University of California, Irvine


United States

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Declaration of Conflict of Interest

DLM is a member of the Scientific Advisory Board of OpenEye Scientific Software and an Open Science Fellow with Silicon Therapeutics.

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Added revised version of paper



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in Journal of Chemical Theory and Computation