Free Energy Calculation And Decomposition Of Hiv-1 Protease-Darunavir Binding By MM-PB/GBSA And Thermodynamic Integration Method

Abstract

Darunavir (DRV) is a novel HIV-1 protease inhibitor which has very high binding affinity with the enzyme (Kd=4.5 X 10-12 M, ΔG=-15.2Kcal/M). Two drug-resistant protease variants MD4 (L10I, G48V, I54V, V82A) and MD2 (V82T, I84V) have been found to decrease the binding affinity with DRV by 1.0kcal/M and 1.5kcal/M respectively. In this study the absolute binding energy of DRV with wild-type protease, MD4 and MD2 is calculated by MM-PB/GBSA method. Relative binding energy of wild-type protease and MD2 with DRV is also calculated by thermodynamic integration method. Free energy decomposition is performed to investigate the mutations’ influence on the protease-DRV binding and how the DRV responses to these mutations. The results suggest that the mutations have distorted the binding pocket of the protease so that the protease residues contributing to the loss of binding energy is not limited to the sites of mutations. The bis-tetrahydrofuranylurethane moiety of DRV is found to maintain its very favorable interaction with the protease atoms even for the MD4 and MD2 variants. On the contrast the amino-benzyl group of DRV has sampled larger conformational space in MD4 and MD2 than in the Wild-type protease that could be the source of the loss of binding energy. Free energy calculations can therefore be an effective way of evaluating relative binding affinities of similar complexes.