In recent years, free energy perturbation (FEP+) has been used to accurately predict the relative binding free energy for small molecule – protein complexes. Here we demonstrate that the same technique can be applied to determine the effect of residue side-chain mutations on protein thermal stability and binding affinity. Specifically, we assessed the performance of protein FEP+ on a curated dataset with more than 350 stabilizing and destabilizing mutations correlating computational ddG predictions with experimental ddG measurements and highlighting the best practices to correct outlier predictions. In addition, we report the application of protein FEP+ to predict differences in binding affinity of wild-type and drug resistant HIV proteases variants to a set of three drug molecules, characterizing the energetic differences of the structural components leading to drug resistance.

Application of free energy perturbation to predict changes in protein stability and affinity upon mutations

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.