Abstract
The emergence of drug resistant mutations due to the selective pressure exerted by antiretrovirals, including protease inhibitors (PIs), remains a major problem in the treatment of AIDS. During PIs therapy, the occurrence of primary mutations in the wild type HIV-1 protease reduces both the affinity for the inhibitors and the viral replicative capacity compared to the wild type (WT) protein, but additional mutations compensate for this reduced viral fitness. To investigate this phenomenon from the structural point of view, we combined Molecular Dynamics and Normal Mode Analysis to analyze and compare the variations of the flexibility of C-alpha atoms and the differences in hydrogen bond (h-bond) network between the WT and double mutants. In most cases, the flexibility profile of the double mutants was more often similar to that of the WT than to that of the related single base mutants. All single mutants showed a significant alteration in h-bond formation compared to WT. Most of the significant changes occur in the border between the flap and cantilever regions. We found that all the considered double mutants have their h-bond pattern significantly altered in comparison to the respective single base mutants affecting their flexibility profile that becomes more similar to that of WT. This WT flexibility restoration in the double mutants appears as an important factor for the HIV-1 fitness recovery observed in patients.
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