RESEARCH ACTIVITY

My research activities and interests concern the application of computational chemistry tecniques, based on  Molecular Dynamics simulation methods, to the  study of bio-macromolecules.

My Phd project mainly concerns the investigation of the structural and dynamical behaviour of sperm-whale Myoglobin, in its wild type and in some mutated forms. In particular we focused on the study of cavities fluctuations and ligand motion relationship.

The research activity during my graduation thesis concerned the study, using Molecular Dynamics simulation methods, of  HIV-1 Protease (HIV-1 PR), some of its mutants and the  complex  of the protease with the inhibitor  A-77003.
HIV-1 PR is a C2 symmetric homodimer of 99 amino acids per chain, it is an important target for anti-AIDS treatment. The inhibitor A-77003 was designed to correspond to this symmetry of the protein; it shows good pharmacological properties.
The behaviour of HIV-1 PR in solution, considering different protonation states of the two catalytic aspartates in the active site, was analysed. The results show that when both aspartatyl residues are deprotonated, a flap opening is observed, that is coupled to a hinge bending of the whole structure around the dimer interface. Conversely,  when only one aspartic acid is protonated,  the flaps remain closed. According to these results, a mechanism for the enzyme activity is proposed.
Three mutants of HIV-1 PR were also analysed. The dynamic behaviour of the mutant associated with pharmacological resistance (R8Q-M46I) shows different characteristics if compared to the native forms and to the other mutants.
The complex of A77003 with the native HIV-1 PR and with the mutated forms has been studied, as well as a long MD simulation of the molecule A-77003 in solution has been performed. On the basis of these results, a mechanism for the ligand binding event has been proposed.
 

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