HIV-1 Protease is an aspartic protease and is one of the key enzymes in HIV, essential for the maturation of new infectious virions emerging from the host helper T-Cell. It is responsible for the cleavage of two HIV polyprotein chains into several distinct proteins including the protease itself, all of which are found in the mature virus.
Structurally it consists of an often
rotationally symmetric dimer with monomoer
subunits of 99 amino acids, resembling a
"bulldog's face". The functionally active
site consists of two aspartic acid residues (one
from each monomer) bound by connected residues
and by a pair of highly mobile "flaps".
The important role of HIV-1 protease in the life
cycle of HIV has made it a crucial target for
developing inhibitors that impede the progress of the
virus within the body. To this effect, several
HIV protease inhibitors (HPIs) have been developed to
obstruct the active site of the protease and thus
impede the cleavage of HIV polyproteins. However
due to the highly mutational characteristics of the
retrovirus, drug resistant strains frequently emerge to
invalidate the efficacy of developed PIs.
We are studying the differential dynamics of several
muational strains of HIV protease along with the wild
type, both as an apo-protease and complexed with
developed PIs, through the application of large scale
molecular dynamics. We hope to elucidate the
difference in dynamical behaviour of wild type with
mutants and determine how this contributes to the
differences in binding affinities between different
strains. We also hope to use themodynamic
integration techniques to calculate difference in exact
binding affinities between different strains.