Structure, dynamics and binding of drug resistance HIV-1 protease with major mutations

Abstract

HIV-1 protease is one of the importance targets for drug development. To date, many protease inhibitors are in clinical used, however, a major problem in the treatment of the HIV infection with protease inhibitor is the development of drug resistance. To understand the molecular basic of drug resistance, the molecular dynamic (MD) simulation of wild-type and mutant proteases complexed with inhibitors, saquinavir and ritonavir, were carried out. The protonation states of the two aspartic residues, Asp25 and Asp25', has been examined by simulating four possible protonation states, non-protonation, mono-protonation and di-protonation of the active site residues and evaluated by means of properties of structure and dynamics, quantum chemical and free energy calculations. The results lead to a conclusion that the appropriate condition is the monoprotonation on Asp25. The MD simulations of a wild-type, G48V, L90M and G48V/L90M of HIV-1 protese with saquinavir and those of a wild-type, V82F, I84V, V82F/I84V of HIV-1 protease with ritonavir have been carried out. It was found that the double mutation of both complexes has the largest impact on the bindings. The conformation changes in double mutant complexes consequently reduce the interaction between drug and protease. The results for both WT and mutants are in a good agreement with the experimental inhibition constant and the resistance fold. Fundamental understanding of the above properties is known to be a prerequisite for the structure-based drug screening and design, both for wild and mutant types.