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

Abstract

During the lifecycle of many enveloped viruses, a nucleocapsid core buds through the cell membrane to acquire an outer envelope of lipid membrane and viral glycoproteins. However, the presence of a nucleocapsid core is not required for assembly of infectious particles. To determine the role of the nucleocapsid core, we develop a coarse-grained computational model with which we investigate budding dynamics as a function of glycoprotein and nucleocapsid interactions, as well as budding in the absence of a nucleocapsid. We find that there is a transition between glycoprotein-directed budding and nucleocapsid-directed budding that occurs above a threshold strength of nucleocapsid interactions. The simulations predict that glycoprotein-directed budding leads to significantly increased size polydispersity and particle polymorphism. This polydispersity can be explained by a theoretical model accounting for the competition between bending energy of the membrane and the glycoprotein shell. The simulations also show that the geometry of a budding particle leads to a barrier to subunit diffusion, which can result in a stalled, partially budded state. We present a phase diagram for this and other morphologies of budded particles. Comparison of these structures against experiments could establish bounds on whether budding is directed by glycoprotein or nucleocapsid interactions. Although our model is motivated by alphaviruses, we discuss implications of our results for other enveloped viruses.

Gaussian curvature and the budding kinetics of enveloped viruses

“…Although the GPs are transmembrane proteins, their 292 assembly is described by the same continuum model as HIV capsid proteins adsorbed to 293 the membrane. Moreover, in our model the conical regions which drive curvature of the 294 model subunit oligomers are located within and below the plane of the membrane, as we 295 found that this arrangement facilitated completion of assembly [1]. We note that the 296 stalling described in the main text was observed for all subunit interaction geometries 297 that we have considered for the alphavirus model [1], as well as in another model for 298 proteins that adsorb onto the membrane [44], suggesting that the barrier is a generic 299 feature of assembly and budding on a membrane.…”

“…Moreover, in our model the conical regions which drive curvature of the 294 model subunit oligomers are located within and below the plane of the membrane, as we 295 found that this arrangement facilitated completion of assembly [1]. We note that the 296 stalling described in the main text was observed for all subunit interaction geometries 297 that we have considered for the alphavirus model [1], as well as in another model for 298 proteins that adsorb onto the membrane [44], suggesting that the barrier is a generic 299 feature of assembly and budding on a membrane. We note that the stalling described in 300 the main text was not observed in some previous budding simulations because they only 301 considered early stages of budding [45][46][47].…”

“…This conclusion is supported by 41 numerical simulations. Figure 2 shows snapshots of a Brownian Dynamics simulation of 42 a simple, coarse-grained model of the budding of the enveloped protein shell of the 43 alphavirus (composed of transmembrane glycoproteins (GPs) [1]. The GPs were Brownian Dynamics simulation of the budding of an enveloped virus using a coarse-grained model of the lipid molecules and capsid proteins of the alpha virus (square inset).…”

“…44 modeled as rigid trimers of truncated cones, with each cone comprising a linear array of 45 six beads of increasing diameter. The cone angle was set so that in the absence of a 46 membrane, the GPs assembled into hollow, roughly icosahedral shells containing 80 47 trimers, though they form larger shells in the presence of a membrane [1]. The 48 membrane was represented by the implicit solvent model of Cooke and Deserno [13].…”

“…Glycoproteins and capsid 308 Our model GPs were designed to roughly match the triangular shape, dimensions and 309 aspect ratio of trimers-of-heterodimers of E1 and E2 GPs in the Sindbis virion 310 [1,50,51]. There are 80 of these trimers arranged with T=4 icosahedral symmetry in the 311 virion structure.…”