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Scientific Computing
Scientific Computing

S. Kashif Sadiq, Molecular and Cellular Modelling Group, Heidelberg Institute for Theoretical Studies (HITS)

Institute for Theoretical Physics, seminar room, Philosophenweg 19

D.W. Heermann, M. Salmhofer, U. Schwarz; Institute for Theoretical Physics, Universität Heidelberg

Retrovirus particle (virion) maturation is a remarkable example of macromolecular assembly coupled to chemical reactions. Infectivity usually requires clustering of multiple transmembrane envelope proteins (Env3) on the virion exterior, yet is only triggered by protease-dependent degradation of a membrane-bound Gag polyprotein lattice on the virion interior through a mechanism that is unclear. High-resolution cryo-electron microscopy has revealed the architecture of the outer shell of the immature virion, but alone does not explain maturation pathways. Modeling could provide insight but current approaches are unable to account simultaneously for both assembly and reactions at this scale. Recently, interaction particle-based reaction diffusion (iPRD) approaches have emerged. These combine space-excluded particle- based isotropic Brownian diffusion with state-changing phenomenological chemical reactions, including the assignment of inter-particle and particle-geometry interaction potentials and make a range of reaction-coupled clustering problems accessible at the required spatiotemporal scale. Here, I develop an approach (1) that integrates cryo-EM and crystallographic data with iPRD models to provide insight into the onset of HIV-1 infectivity from an immature virion. The model implements an ultra-coarse-graining (UCG) scheme based on the structural dimensions of each molecule to treat entire proteins at near-single particle resolution. It includes binding stoichiometry and lattice symmetries and can follow transmembrane Env3 diffusion in the presence of a monotopic truncated Gag lattice composed of membrane-bound matrix (MA) proteins linked to capsid (CA) subunits and freely diffusing protease (PR) enzymes. Simulations suggest that initial immobility of Env3 is conferred through lateral caging by matrix trimers vertically coupled to the underlying hexameric capsid layer. Gag cleavage by PR vertically decouples the matrix and capsid layers, induces both MA and Env3 diffusion, and permits Env3 clustering. Spreading across the entire membrane surface reduces crowding, in turn, enhancing the effect and suggests how infectivity can be achieved. Finally, I will outline how such a model could both be extended to orientation-specific assembly problems and then coupled to atomistic MD and BD simulations and physical geometry models within a multiscale framework that would then more completely handle the complexity of such phenomena.

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