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A major problem in the antiretroviral treatment of HIV-infections with protease-inhibitors is the emergence of resistance, resulting from the occurrence of distinct mutations within the protease molecule. In the present work we investigated the structural properties of a triple mutant (I54V-V82A-L90M) and a double mutant (V82A-L90M) that both confer strong resistance to ritonavir (RTV), but not to amprenavir (APV). For the unliganded double mutant protease molecular dynamics simulations revealed a contraction of the ligand binding pocket, which is enhanced by the I54V mutation. The observed displacement of backbone atoms of the 80s loops (residues 80-85 and 80'-85' of the dimer) was found to primarily affect binding of the larger RTV molecule. The pocket contraction detected for the unbound protease upon mutation is also observed in the presence of APV, but not of RTV. As a consequence, the protein-ligand contacts lost upon the V82A mutation are restored by 80s loop motions for the APV-bound, but not for the RTV-bound form. RTV binding is therefore both hampered in the initial recognition step due to the poor fit of the bulky inhibitor into the small pocket of the mutant free protease and by the loss of protein-ligand interactions in the RTV-bound protease. The synergistic nature of both effects offers an explanation for the high level of resistance observed. These findings demonstrate that large inhibitors, which tightly bind to wild-type protease, may nevertheless be prone to the emergence of resistance in the presence of particular patterns of mutations. This information should be helpful for the design of novel and more effective drugs, e.g., by targeting different residues or by developing allosteric inhibitors that are capable of regulating protease dynamics.

Effects of the V82A and I54V mutations on the dynamics and ligand binding properties of HIV-1 protease