Viral morphogenesis, the phenomenon by which viruses reorganize their internal macromolecular structure in space and time across their lifecycle, is a complex process that is not quantitatively understood. HIV maturation, in particular, involves detailed atomistic processes such as protein-ligand recognition and cleavage that triggers large-scale macromolecular spatiotemporal rearrangement such as capsid self-assembly and RNA-modulated nucleocapsid condensation leading to infectious virus particles (virions) in a sequence of morphological changes that need to be carefully timed. Many antiretroviral inhibitors have been developed to stop maturation but their efficacy has been undermined by the emergence of drug resistant mutations. Furthermore, the effect of such inhibitors on the internal spatiotemporal viral dynamics is unknown. In order to quantitatively understand the determinants of maturation, inhibition and mutational resistance it is vital to construct a complete physics-based model of the maturation process. This requires detailed understanding of how all the relevant viral molecular constituents interact with each other at the atomistic level, how this is affected by drug interactions and mutations in proteins and how this carries over to the large-scale cleavage and self-assembly process. This project aims at deriving a multi-scale computer model of HIV maturation, integrating thermodynamic and kinetic binding data from massively parallel detailed molecular dynamics simulations of viral protein-protein and protein-drug interactions with particle-based reaction diffusion kinetics simulations describing the internal processing and remodeling in an entire virion explicitly in space and time. We will also investigate what happens if the morphological sequence is perturbed and use this to discover novel allosteric targets followed by implementing a high-throughput virtual and experimentally validated drug-screening program towards HIV eradication therapy.
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