Investigating the mutation resistance of nonnucleoside inhibitors of HIV-RT using multiple microsecond atomistic simulations

Inhibiting HIV reverse transcriptase through the use of nonnucleoside reverse transcriptase inhibitors (NNRTIs) has become an essential component in drug regimens for the treatment of HIV. Older NNRTIs, such as nevirapine, are structurally rigid, exhibiting decreased inhibitory function on development of common mutations in the NNRTI-binding pocket, which is located around 10 Å from the catalytically active binding site. The newer generation of drugs, such as rilpivirine, are more flexible and resistant to binding pocket mutations but the mechanism by which they actually inhibit protein function and avoid mutations is not well-understood. To this end, we have performed 2-2.4 μs simulations with explicit solvent in an isobaric-isothermal ensemble of six different systems: apo wild-type, apo K103N/Y181C mutant, nevirapine-bound wild-type, nevirapine-bound mutant, rilpivirine-bound wild type, and rilpivirine-bound mutant. Analysis of protein conformations, principal components of motion, and mutual information between residues points to an inhibitory mechanism in which the primer grip stretches away from the catalytic triad of aspartic acids necessary for polymerization of HIV-encoding DNA, but is still unable to reveal a specific structural mechanism behind mutation resistance.