Deciphering complex mechanisms of resistance and loss of potency through coupled molecular dynamics and machine learning.
Drug resistance threatens many critical therapeutics through mutations in the drug target. The molecular mechanisms by which combinations of mutations, especially involving those distal from the active site, alter drug binding to confer resistance are poorly understood and thus difficult to counteract. A machine learning strategy was developed that couples parallel molecular dynamics simulations and experimental potency to identify specific conserved mechanisms underlying resistance. A series of 28 HIV-1 protease variants with 0-24 substitutions each were used as a rigorous model of this strategy. Many of the mutations were distal from the active site and the potency of variants to a drug (darunavir) varied from low pM to near {micro}M. With features extracted from the simulations, elastic network machine learning was applied to correlate physical interactions with loss of potency and succeeded to within 1 kcal/mol of experimental affinity for both the training and test sets, outperforming MM/GBSA calculations. Feature reduction resulted in a model with 4 specific features that describe interactions critical for potency for all 28 variants. These predictive features, that specifically vary with potency, occur throughout the enzyme and would not have been identified without dynamics and machine learning. This strategy thus captures the conserved dynamic mechanisms by which complex combinations of mutations confer resistance and identifies critical features that serve as bellwethers of loss of inhibitor potency. Machine learning models leveraging molecular dynamics can thus elucidate mechanisms of drug resistance that confer loss of affinity and will serve as predictive tools in future drug design.