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Abstract

The orthogonal space random walk (OSRW) algorithm is generalized to be the orthogonal space tempering (OST) method via the introduction of the orthogonal space sampling temperature. A double-integration recursion method enables practically efficient and robust OST free energy calculations, augmented by a θ-dynamics approach. The double-integration OST method performs alchemical free energy simulations, to calculate the free energy difference between benzyl phosphonate and difluorobenzyl phosphonate in aqueous solution, to estimate the solvation free energy of the octanol molecule, and to predict the nontrivial Barnase-Barstar binding affinity change induced by the Barnase N58A mutation. The DI-OST method robustly enables practically efficient free energy predictions, particularly when strongly coupled slow environmental transitions are involved. A classical set of p38α MAP Kinase inhibitors are also employed as a test bed for evaluating relative binding affinity calculation methods. Throughout the molecular dynamics (MD) sampling no human intervention was involved

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