Multiscale Simulation of HIV-1 Virion Release and Maturation

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PROJECT SUMMARY Certain key processes in the HIV-1 viral lifecycle are still poorly or incompletely understood. These processes include the release of the virion from infected cells, the virion maturation, and the genome packaging within the virion as it matures. These processes are highly complex, involving sequential multiprotein and nucleic acid assembly and disassembly, as well as protein-mediated membrane interactions. Computationally simulating these processes thus requires the use of both all-atom (AA) and coarse-grained (CG) molecular dynamics (MD) methods in an innovative multiscale fashion in order to access the relevant spatial and temporal scales. The Voth group will develop and carry out both AA and CG simulations to study the large viral protein complexes relevant to these important problems in the HIV-1 life cycle. The specific processes to be studied are involved in the viral release and maturation processes, specifically the proteolytic cleavage of Gag and capsid assembly within the virion (Aim 1), the virion component reorganization and ribonucleoprotein complex condensation upon maturation (Aim 2), and the latter stage dynamics of virion release from infected cells (Aim 3). The computational model development and multiscale simulation efforts will be integrated and iterated with the experimental studies of two leading experimental investigators (John Briggs and Hans-Georg Kräusslich) and one independently funded collaborator (James Hurley). These novel and powerful multiscale computer simulations – and the collaborative effort with experimentalists – will provide new insight into the dynamical aspects of HIV-1 release and maturation which are not readily accessible to the experimental (or computational) efforts alone.