DeepBAR: A Fast and Exact Method for Binding Free Energy Computation.

Abstract

The fast and accurate calculation of standard binding free energy has many important applications. Existing methodologies struggle at balancing accuracy and efficiency. We introduce a new method to compute binding free energy using deep generative models and the Bennett acceptance ratio method (DeepBAR). Compared to the rigorous potential of mean force (PMF) approach that requires sampling from intermediate states, DeepBAR is an order-of-magnitude more efficient as demonstrated in a series of host-guest systems. Notably, DeepBAR is exact and does not suffer from approximations for entropic contributions used in methods such as the molecular mechanics energy combined with the generalized Born and surface area continuum solvation (MM/GBSA). We anticipate DeepBAR to be a valuable tool for computing standard binding free energy used in drug design.