Over the last decade of AIDS therapy, the HIV-1 protease has emerged as one of the key targets of anti-retroviral inhibitors, owing to its key role in the life-cycle of the virus. The protease cleaves viral polyprotein chains resulting in virion maturation and infectivity. The first stage of this process is the association of such chains containing embedded pseudo-folded protease monomers, followed by the intramolecular autocatalytic cleavage of the protease out of the polyprotein chains. Whilst, the structure, dynamics and function of mature/free HIV-1 protease have been extensively studied at the atomistic level, the molecular structure and binding mechanism of the embedded autocatalytic protease are unknown. Using large scale fully atomistic molecular dynamics simulations on the microsecond timescale, afforded by the computational infrastructure of GPUGrid, the transient structure, dynamics and auto-binding mechanism of embedded HIV-1 protease will be investigated. The aim of these investigations is to distinguish at a molecular level (a) the gating mechanism of mature HIV-1 protease in response to ligands (b) the gating mechanism of intramolecular N-terminal association of the embedded HIV-1 protease and (c) the feasibility of intramolecular C-terminal cleavage by the protease. The release of mature HIV-1 protease is a critical rate-limiting step in the maturation of the virus. Successful inhibition of this stage of the viral life-cycle may lead to a potent increase in the efficacy of AIDS therapy. Unfortunately, structure-based inhibitors designed for the mature/free protease are ineffective against the embedded-protease. A final aim of this investigation will thus be to identify an ensemble of macromolecular structures that could be used as pharmacophores in the development of inhibitors that target the embedded protease.
Fields of science
Call for proposal
See other projects for this call