Simulations Show that Virus Assembly and Budding Are Facilitated by Membrane Microdomains

Abstract

For many viruses, assembly and budding occur simultaneously during virion formation. Understanding the mechanisms underlying this process could promote biomedical efforts to block viral propagation and enable use of capsids in nanomaterials applications. To this end, we have performed molecular dynamics simulations on a coarse-grained model that describes virus assembly on a fluctuating lipid membrane. Our simulations show that the membrane can promote association of adsorbed subunits through dimensional reduction, but it also introduces thermodynamic and kinetic effects that can inhibit complete assembly. We find several mechanisms by which membrane microdomains, such as lipid rafts, reduce these effects, and thus, enhance assembly. We show how these predicted mechanisms can be experimentally tested. Furthermore, the simulations demonstrate that assembly and budding depend crucially on the system dynamics via multiple timescales related to membrane deformation, protein diffusion, association, and adsorption onto the membrane.

Membrane Charge Directs the Outcome of F-BAR Domain Lipid Binding and Autoregulation

“…One mechanism for this behavior, supported by our single particle electron microscopy data, is that the F-BAR domain is biased towards a deformation-promoting (concave surface-down) conformation at low PI(4,5)P 2 . Another nonexclusive possibility is that at high PI(4,5)P 2 , the organization or rigidity of membrane itself may inhibit assembly, either by forming lipid clusters of a size that disfavor deformation, or by restricting dynamic rearrangements of individual proteins into higher assemblies (Ruiz-Herrero and Hagan, 2015). Assessing the relative contributions of these forces will require developing a theoretical framework that describes the nucleation, oligomerization, and lipid-binding behaviors of Nwk.…”

Mechanisms of Virus Assembly

“…Interestingly, the ability of the membrane to promote assembly depended non-monotonically on the bending modulus κ , with budding suppressed by membrane bending energy at high κ or entropic membrane fluctuations at low κ (151). Ruiz-Herrero and Hagan (153) considered an implicit solvent lipid bilayer membrane model and pentameric subunits that adsorb onto the membrane and assemble to form a dodecahedron (Fig. 7D).…”

Molecular dynamics simulations of large macromolecular complexes

“…However, processes during virus replication that are inherently slow and involve large systems, such as virus assembly and budding [46], membrane fusion, virus maturation, uncoating of viral capsids, and nuclear entry, represent the current threshold for MD simulations of viruses. In particular, studies on host-pathogen interactions involving large numbers of proteins [47], are still scarce, yet essential to the investigation of virus replication cycles, as well as for the development of drugs and the engineering of viruses for gene therapy.…”