title: Reaction-diffusion basis of retroviral infectivity.
abstract: Retrovirus particle (virion) infectivity requires diffusion and clustering of multiple transmembrane envelope proteins (Env3) on the virion exterior, yet is triggered by protease-dependent degradation of a partially occluding, membrane-bound Gag polyprotein lattice on the virion interior. The physical mechanism underlying such coupling is unclear and only indirectly accessible via experiment. Modelling stands to provide insight but the required spatio-temporal range far exceeds current accessibility by all-atom or even coarse-grained molecular dynamics simulations. Nor do such approaches account for chemical reactions, while conversely, reaction kinetics approaches handle neither diffusion nor clustering. Here, a recently developed multiscale approach is considered that applies an ultra-coarse-graining scheme to treat entire proteins at near-single particle resolution, but which also couples chemical reactions with diffusion and interactions. A model is developed of Env3molecules embedded in a truncated Gag lattice composed of membrane-bound matrix proteins linked to capsid subunits, with freely diffusing protease molecules. Simulations suggest that in the presence of Gag but in the absence of lateral lattice-forming interactions, Env3diffuses comparably to Gag-absent Env3Initial immobility of Env3is conferred through lateral caging by matrix trimers vertically coupled to the underlying hexameric capsid layer. Gag cleavage by protease vertically decouples the matrix and capsid layers, induces both matrix and Env3diffusion, and permits Env3clustering. Spreading across the entire membrane surface reduces crowding, in turn, enhancing the effect and promoting infectivity.This article is part of the themed issue 'Multiscale modelling at the physics-chemistry-biology interface'.
authors.affiliation: Infection Biology Unit, Universitat Pompeu Fabra, Barcelona Biomedical Research Park (PRBB), C/Doctor Aiguader 88, 08003 Barcelona, Spain Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), Schloss-Wolfsbrunnenweg 35, 69118 Heidelberg, Germany kashif.sadiq@h-its.org syedkashifsadiq@gmail.com.
authors.forename: S Kashif
authors.identifier: http://orcid.org/0000-0002-5112-0307
authors.initials: SK
authors.lastname: Sadiq
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D004058:Diffusion; D015683:Gene Products, gag / Q000737:chemistry* / Q000502:physiology* / Q000648:ultrastructure; D008954:Models, Biological; D008956:Models, Chemical; D011485:Protein Binding; D012190:Retroviridae / Q000737:chemistry* / Q000502:physiology / Q000648:ultrastructure; D014759:Viral Envelope Proteins / Q000737:chemistry* / Q000502:physiology / Q000648:ultrastructure; D014771:Virion / Q000737:chemistry* / Q000502:physiology / Q000648:ultrastructure; D014774:Virulence / Q000502:physiology
chemical_list: D015683:Gene Products, gag; D014759:Viral Envelope Proteins
keywords: Brownian dynamics; coarse-graining; macromolecular self-assembly; reaction–diffusion; synthetic virology