Protease inhibitors designed to bind to protease have become major anti-AIDS drugs. Unfortunately, the emergence of viral mutations severely limits the long-term efficiency of the inhibitors. The resistance mechanism of these diversely located mutations remains unclear.
Here I use an elastic network model to probe the connection between the global dynamics of HIV-1 protease and the structural distribution of drug-resistance mutations. The models for study are the crystal structures of unbounded and bound (with the substrate and nine FDA approved inhibitors) forms of HIV-1 protease. Coarse-grained modeling uncovers two groups that couple either with the active site or the flap. These two groups constitute a majority of the drug-resistance residues. In addition, the significance of residues is found to be correlated with their dynamical changes in binding and the results agree well with the complete mutagenesis experiment of HIV-1 protease.
The dynamic study of HIV-1 protease elucidates the functional importance of common drug-resistance mutations and suggests a unifying mechanism for drug-resistance residues based on their dynamical properties. The results support the robustness of the elastic network model as a potential predictive tool for drug resistance.
BMC Structural Biology 2011, 11:31 doi:10.1186/1472-6807-11-31