文摘
To understand the basis of drug resistance of the HIV-1 protease, molecular dynamic (MD) and free energycalculations of the wild-type and three primary resistance mutants, V82F, I84V, and V82F/I84V, of HIV-1protease complexed with ritonavir were carried out. Analysis of the MD trajectories revealed overall structuresof the protein and the hydrogen bonding of the catalytic residues to ritonavir were similar in all four complexes.Substantial differences were also found near the catalytic binding domain, of which the double mutantcomplex has the greatest impact on conformational changes of the protein and the inhibitor. The tip of theHIV-1 protease flap of the double mutant has the greater degree of opening with respect to that of theothers. Additionally, the phenyl ring of Phe82 moves away from the binding pocket S1', and theconformational change of ritonavir subsite P1' consequently affects the cavity size of the protein and theconformational energy of the inhibitor. Calculations of binding free energy using the solvent continuummodel were able to reproduce the same trend of the experimental inhibition constant. The results show thatthe resistance mutants require hydrophobic residues to maintain the interactions in the binding pocket. Changesof the cavity volume correlate well with free energy penalties due to the mutation and are responsible forthe loss of drug susceptibility.