Computationalinvestigation of HIV-1 protease dynamics by comparing the effects of mutation, force fields and pressure

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AIDS, one of the major epidemics of the human society has been the constant worry. UNAIDS projection shows the existence of millions of AIDS patients at the end of 2008 with high mortality rate and fresh infections in coming days. All the FDA approved drugs are getting resistant against the clever HIV because of its frequent mutations. Hence there is an urgent need of developing new drugs with greater potential. AIDS is mainly due to the infection of retrovirus HIV. It infects the CD4+ cells of immune system thereby reducing its number to reach an immune deficiency condition. The viral life cycle is controlled by the activities of its essential proteins like gp41, gp120, HIV-RT, HIV-IN, and HIV-pr. Each protein has substantial role on the viral life cycle to be continued. The present thesis focuses on the protein HIV-pr, which is important for the cleavage of Gag and Gag-Pol polyproteins to form the smaller structural and functional proteins. Structurally, the homodimeric aspartyl protease has 198 residues in both chains with the catalytic aspartate in the dimer interface. Glycine rich flexible flaps cap the active site of HIV-pr, which controls the accession of ligands and size of the active site. The conformation of the protein plays a pivotal role in ligand binding and the catalytic process, which is affected by the rapid point mutations and various physiological parameters. In the present thesis, the conformational dynamics of HIV-pr is being studied in an atomistic detail by MD simulations. Both biological and technical aspects of the protein conformation and dynamics have been explored. With regards to the biological aspect, initially the effect of I47V mutation on the dynamics of HIV-pr and its effect on ligand (JE-2147) binding were investigated and was observed to have both direct and indirect effects on drug resistance. Also it gave the clues for increase ddynamics under high pressure compared to normal condition. It was observed that protein under high pressure validate the general decrease in the proteinDs structural degrees of freedom and pressure plays a crucial role in reducing the structural variability in proteins. Coming to the technical aspects, we studied the effects of polarization and the difference in force fields on the protein conformation. It was found that, polarizations of force fields influence both the global and specific local motions of protein and solvent thereby increasing the rigidity in proteins. Also the water movements around different types of residues are marked to be different and are high for charged residues. Comparative study of the HIV-pr dynamics by multiple force fields shed light on the difficulty in modeling dynamics of proteins with flexible binding site and in silico drug design against flexible receptors. The complex dynamics of HIV-pr can be sensitive enough to the force field difference. Hence a careful examination with different simulation parameters is required to conclude regarding the biological functions drawn from MD simulation studies. Altogether, these studies indicate that conformational dynamics of HIV-pr is sensitive enough to the simulation setups and force fields difference. Also mutation in some specific region has both direct and indirect effects on the conformation and dynamics of HIV-pr. The outcome of the thesis has noteworthy applicat...
Supervisor: R Swaminathan