Item Details

Identifying Ligand Binding Sites and Poses Using GPU-Accelerated Hamiltonian Replica Exchange Molecular Dynamics

Wang, Kai
Format
Thesis/Dissertation; Online
Author
Wang, Kai
Advisor
Shirts, Michael
Abstract
We present a method to identify small molecule ligand binding sites and orientations to a given protein crystal structure using GPU-accelerated Hamiltonian replica exchange molecular dynamics simulations. The Hamiltonians used vary from the physical end state of protein interacting with the ligand to an unphysical end state where the ligand does not interact with the protein. As replicas explore the space of Hamiltonians interpolating between these states the ligand can rapidly escape local minima and explore potential binding sites. Geometric restraints keep the ligands from leaving the vicinity of the protein and an alchemical pathway designed to increase phase space overlap between intermediates ensures good mixing. Because of the rigorous statistical mechanical nature of the Hamiltonian exchange framework, we can also extract binding free energy estimates for all putative binding sites. We present results of this methodology on the T4 lysozyme L99A model system for three known ligands and one nonbinder as a control, using an implicit solvent. We find that our methodology identifies known crystallographic binding sites consistently and accurately for the small number of ligands considered here and gives free energies consistent with experiment. We are also able to analyze the contribution of individual binding sites to the overall binding affinity. Our methodology points to near term potential applications in early-stage drug discovery.
Language
English
Date Received
20161209
Published
University of Virginia, Department of Chemical Engineering, MS (Master of Science), 2016
Published Date
2016-12-12
Degree
MS (Master of Science)
Collection
Libra ETD Repository
Logo for Creative Commons Attribution LicenseCreative Commons Attribution License

Availability

Read Online