Determining the molecular mechanisms of HIV-1 maturation

点击翻译按钮获取中文摘要

Project Abstract Before a newly budded HIV-1 particle becomes fusogenic (and infective) it must undergo maturation. During maturation the contents of the virion transform from a spherical shell into a conical structure after a series of cleavages of the 55 kDa Gag polyprotein by the viral protease. Proteolytic processing starts at the site between the spacer peptide 1 (SP1) and the nucleocapsid (NC) and culminates in the separation of SP1 from the capsid protein (CA). The initial cleavage event effectively separates the NC-gRNA layer from the viral membrane inducing gRNA condensation. The last event activates a molecular switch that triggers a late maturation event, namely the assembly of the mature HIV-1 capsid around the ribonucleic protein. During maturation, the matrix protein (MA), that is embedded to the viral membrane via a myristoyl group, is cleaved from CA, resulting in reordering of the MA lattice and alteration of the composition of the lipid membrane. Although several structures of immature and mature CA and MA hexamers have been solved by sub tomogram averaging, the molecular mechanism connecting the multiple events that occur during HIV-1 maturation are still unclear. Here, we propose to utilize full-scale molecular dynamics simulations, integrating shaped-based coarse- grained and atomistic methods, to determine motion-structures that reveal the mechanistic details of HIV-1 virion maturation. Results from the simulations will inform the engineering of protein mutants for structural analysis and guide the experimental design of functional analyses and testing of hypotheses derived from the molecular simulations.