The traditional alchemical free energy methods of free energy perturbation and thermodynamic integration are robust and accurate, however they suffer from issues surrounding poor convergence and scalability. Although recent trends have improved algorithms to address the convergence issues (i.e. replica exchange techniques), scalability remains an issue. Recently, we introduced biasing potential replica exchange multisite λ-dynamics (BP-REX MSλD) to overcome the issues with convergence of large perturbations, and now have expanded our method to address the scalability issues. Using the CHARMM molecular dynamics package, we performed an exhaustive exploration of the chemical space for 512 inhibitors of HIV-RT in a few simulations. Through this exploration, we were able to identify 95 more potent inhibitors than the reference (0.056 μM) against HIV-RT. Compared to experimental EC<sub>50</sub> values, we accurately recapitulated the binding affinities, with a root mean square error (RMSE) of 0.68 kcal/mol. Further, we show that coupling ligand permutations with protein mutations is possible using BP-REX MSλD for large-scale protein-ligand binding affinity calculations.

Using multisite lambda dynamics for the calculation of 512 binding free energies of HIV-RT in ~1.5 μs

251st National Meeting (2016)

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