434726 How Tightly Focused Is the Configurational Ensemble of Small Molecule Ligands Bound to Proteins?

Thursday, November 12, 2015: 8:47 AM
255B (Salt Palace Convention Center)
Kai Wang1 and Michael R. Shirts1,2, (1)Department of Chemical Engineering, University of Virginia, Charlottesville, VA, (2)Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, CO

We show how Hamiltonian replica exchange molecular dynamics simulations can be used to construct a ensemble of ligand binding locations. We allow the ligand to sample all available conformational space by applying a variety of Hamiltonian exchange, Monte Carlo, and other sampling techniques to escape local binding minima.  Because of the rigorous nature of the statistical mechanical sampling, we can also extract binding free energy estimates at all putative binding sites. From these simulations, we can construct a ligand binding density, and attempt to predict the experimental binding location(s) from this density.

For the T4 lysozyme L99A model system, we find that this binding density gives discrete clusters, is robust over multiple simulation runs and that we can distinguish binders from non-binders, with free energies consistent with experiment.  For simulations of the ASTEX diverse data set, 37% of the time the most populated cluster corresponds to the experimental binding site, and in 76% of the time one of the top three most populated clusters corresponds to the experimental binding site.

We propose that these binding ensembles may approximate ligand binding ensembles actually occurring in many protein-ligand complexes. We present theoretical arguments that such solution phase ensembles are not inconsistent with crystal structures showing only single bound configurations, and discuss the implications of these results for fragment-based drug design and in proteins whose natural function it is to bind weakly to small molecules like human serum albumin.

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See more of this Session: Thermophysical Properties of Biological Systems
See more of this Group/Topical: Engineering Sciences and Fundamentals