Characterizing drug resistance using geometric ensembles from HIV protease dynamics

The use of antiretrovirals (ARVs) has drastically improved the life quality and expectancy of HIV patients since their introduction in health care. Several millions are still afflicted worldwide by HIV and ARV resistance is a constant concern for both healthcare practitioners and patients, as while treatment options are finite, the virus constantly adapts and selects for resistant viral strains under the pressure of drug treatment. The HIV protease is a crucial enzyme that processes viral polyproteins into their functional form, and has been a game changing drug target since the first application. Due to similarities in protease inhibitor designs, drug cross-resistance is not uncommon across ARVs of the same class. It is known that resistance against protease inhibitors is associated with a wider active site, but results from our large scale molecular dynamics analysis further show, for the first time, that there are regions of local expansions and compactions associated with high levels of resistance conserved across eight different protease inhibitors visible in their complexed form in closed receptor conformations. The method developed here is novel, supplementary to the methods of nonsynonymous mutation analysis, and should be applicable in analyzing the structural consequences of mutations in other contexts.