Traditional free energy calculation methods are known for their drawbacks in speed and scalability. Here, we report on the development of biasing potential replica exchange multi-site λ-dynamics (BP-REX MSλD), which is a free energy method that is capable of performing multiple simultaneous alchemical free energy transformations. Compared to the traditional MSλD algorithm, BP-REX MSλD improves the sampling of alchemical perturbations (λ-space) by as much as 5 fold, and it enables relatively large alchemical perturbations spanning volume changes by as much as 60 Å<sup>3</sup>. We applied BP-REX MSλD to a series of HIV RT inhibitors and demonstrated the feasibility of performing near simultaneous calculation of binding free energies of more than 1000 compounds in a single molecular dynamics simulation, while maintaining comparable accuracy (~1-2 kcal/mol error) to existing free energy methods. Our results suggest that the BP-REX MSλD algorithm is a highly efficient and scalable free energy method, which when utilized will enable routine free energy calculations on the order of thousands of compounds, while using only a limited quantity of computational resource.

Biasing potential replica exchange multisite λ-dynamics: Toward scalable and simultaneous free energy calculations of more than 1000 compounds

249th National Meeting (2015)

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