Allosteric Control of Icosahedral Capsid Assembly

Abstract

During the lifecycle of a virus, viral proteins and other components self-assemble to form an ordered protein shell called a capsid. This assembly process is subject to multiple competing constraints, including the need to form a thermostable shell while avoiding kinetic traps. It has been proposed that viral assembly satisfies these constraints through allosteric regulation, including the interconversion of capsid proteins among conformations with different propensities for assembly. In this article we use computational and theoretical modeling to explore how such allostery affects the assembly of icosahedral shells. We simulate assembly under a wide range of protein concentrations, protein binding affinities, and two different mechanisms of allosteric control. We find that, above a threshold strength of allosteric control, assembly becomes robust over a broad range of subunit binding affinities and concentrations, allowing the formation of highly thermostable capsids. Our results suggest that allostery can significantly shift the range of protein binding affinities that lead to successful assembly, and thus should be accounted for in models that are used to estimate interaction parameters from experimental data.

Why Enveloped Viruses Need Cores—The Contribution of a Nucleocapsid Core to Viral Budding

“…This behavior is indicative of kinetic trapping, known to occur in assembly reactions at high concentrations or binding affinities (73,74). The ability of an inactive conformation to avoid this trap is consistent with simulations of bulk assembly (59,60), and the ability of budding to proceed in the presence of high subunit concentrations (when conformational changes are accounted for), which is consistent with the observation of high densities of GPs in the membranes of cells infected with Sindbis virus (75).…”

“…Experiments on several viral families suggest that viral proteins interconvert between ''assembly active'' and ''assembly inactive'' conformations, which are respectively compatible or incompatible with assembly into the virion (56)(57)(58). Computational models suggest that such conformational dynamics can suppress kinetic traps (59,60). Conformational changes of the alphavirus GPs E1 and E2 are required for dimerization in the cytoplasm, and it has been proposed that the GPs interconvert between assembly inactive and assembly active conformations (58), possibly triggered by interaction with NC proteins (18).…”

Mechanism of action of HBV capsid assembly modulators predicted from binding to early assembly intermediates

“…In contrast, the assembly-incompetent Y132A mutant tetramer 22 showed similar FOA with the hexamer state as the WT tetramer (21%), suggesting that the assembly inhibition is not caused by altered inter-dimer orientation. We hypothesize that the "assembly active" conformation is a tetramer that adopts a more "hexamer-like" conformation, in agreement with the theory of allosteric assembly 18,19,35 . The frequency of such conformations is increased for the V124W mutant, explaining its acceleration of the capsid assembly kinetics.…”

“…Nucleocapsid assembly is an important event in the viral replication cycle 2, 12 . It is governed by weak association energies between core protein subunits and is highly sensitive to the assembly conditions 18,35,39 . It has been proposed that for HBV, the assembly is nucleated by an intermediate of three dimers, a triangular hexamer shown in Figure 1C, and that nucleus formation requires the adoption of a rare "assembly-active" conformation by a capsid protein dimer [17][18][19] .…”

Stochastic Yield Catastrophes and Robustness in Self-Assembly

“…Second, the formation of a structure must be initiated by a nucleation event ('nucleation'). Due to cooperative or allosteric effects in binding, there might be a significant nucleation barrier [15][16][17][18][19] . Third, following nucleation, structures grow via aggregation of substructures ('growth').…”