(56i) On the Collective Nature of Viral Protein Assembly and Membrane Lipid Reorganization during HIV-1 Budding

Enveloped viruses are biological “nanoparticles” that hijack cellular machinery to package, protect, and deliver viral materials between cells. One fascinating example is human immunodeficiency virus type-1 (HIV-1), in which Gag polyproteins are known to self-assemble into an ordered protein lattice at the plasma membrane interface while coordinating a dimer of viral ribonucleic acid (RNA). The assembly is commensurate with an extracellular protrusion that eventually forms a spherical particle (or “bud”) that releases from the host cell. Understanding the biophysical basis that enables viruses to recruit selective cargo and form protective membranes through budding can inspire new directions for virus-inspired nanocarriers in drug and gene therapy applications. Interestingly, viral particles are known to have elevated concentrations of raft-associated lipids compared to plasma membranes, thereby suggesting that a relationship between protein assembly and membrane composition exists. To investigate this process, we systematically derive coarse-grained (CG) models of proteins and lipids and use enhanced sampling approaches in order to access biologically-relevant spatiotemporal scales that are inaccessible to conventional molecular dynamics (MD) simulations. First, we reveal nonlinear relationships between protein assembly rates, structural pleomorphism, and membrane stiffness on flat substrates, in which a “resonance” between optimal assembly and membrane flexural motion emerges due to entropic forces. Furthermore, distinct shifts in the resonance appear as the Gaussian curvature of the membrane increases, which appear to favor increasing fractions of stiff lipid domains. We propose a model in which the feedback between protein assembly and membrane deformation requires gradual recruitment of raft-associated lipids. Our findings suggest an alternative budding process that proceeds even in the absence of conventional line tension arguments. The fundamental insights from this study have implications for both soft materials engineering and biomedical applications.