Consistent Prediction of Mutation Effect on Drug Binding in HIV‑1 Protease Using Alchemical Calculations

Despite
a large number of antiretroviral drugs targeting HIV-1 protease for
inhibition, mutations in this protein during the course of patient
treatment can render them inefficient. This emerging resistance inspired
numerous computational studies of the HIV-1 protease aimed at predicting
the effect of mutations on drug binding in terms of free binding energy
ΔG, as well as in mechanistic terms. In this
study, we analyze ten different protease-inhibitor complexes carrying
major resistance-associated mutations (RAMs) G48V, I50V, and L90M
using molecular dynamics simulations. We demonstrate that alchemical
free energy calculations can consistently predict the effect of mutations
on drug binding. By explicitly probing different protonation states
of the catalytic aspartic dyad, we reveal the importance of the correct
choice of protonation state for the accuracy of the result. We also
provide insight into how different mutations affect drug binding in
their specific ways, with the unifying theme of how all of them affect
the crucial drug binding regions of the protease.