Optimization of protein-ligand binding free energy is a central goal of small molecule drug discovery. Yet molecular mechanics force fields that are commonly used in computer-aided drug design efforts treat non-bonded interactions using a limited library of empirical parameters that are developed for small molecules and do not necessarily account for polarization in larger drug molecules or proteins. Using linear-scaling density functional theory and atoms-in-molecule electron density partitioning, environment-specific charges and vdW parameters are derived directly from quantum mechanical calculations for use in free energy simulations for drug discovery [1]. The proposed methods significantly reduce the number of empirical parameters needed to construct molecular mechanics force fields, naturally include polarization effects in charge and vdW parameters, and scale well to systems comprising thousands of atoms, including entire proteins [2,3]. The feasibility and benefits of this approach are demonstrated by computing the relative binding free energies of indole and benzofuran to the L99A mutant of T4 lysozyme. [1] D. J. Cole, J. Z. Vilseck, J. Tirado-Rives, M. C. Payne, W. L. Jorgensen, in preparation (2015) [2] L. P. Lee, D. J. Cole, C.-K. Skylaris, W. L. Jorgensen, M. C. Payne, Journal of Chemical Theory and Computation, 9, 2981 (2013) [3] L. P. Lee, N. Gabaldon Limas, D. J. Cole, M. C. Payne, C.-K. Skylaris, T. A. Manz, Journal of Chemical Theory and Computation, 10, 5377 (2014)

Biomolecular force field parameterization via atoms-in-molecule electron density partitioning

251st National Meeting (2016)

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