A theoretical model successfully identifies features of hepatitis B virus capsid assembly

The capsids of most spherical viruses are icosahedral, an arrangement of mu ltiples of 60 subunits, Though it is a salient point in the life cycle of a ny virus, the physical chemistry of virus capsid assembly is poorly underst ood. We have developed general models of capsid assembly that describe the process in terms of a cascade of low order association reactions. The model s predict sigmoidal assembly kinetics, where intermediates approach a low s teady state concentration for the greater part of the reaction. Features of the overall reaction can be identified on the basis of the concentration d ependence of assembly. In simulations, and on the basis of our understandin g of the models, we find that nucleus size and the order of subsequent "elo ngation" reactions are reflected in the concentration dependence of the ext ent of the reaction and the rate of the fast phase, respectively. The react ion kinetics deduced for our models of virus assembly can be related to the assembly of any "spherical" polymer. Using light scattering and size exclu sion chromatography, we observed polymerization of assembly domain dimers o f hepatitis B virus (HBV) capsid protein. Empty capsids assemble at a rate that is a function of protein concentration and ionic strength. The kinetic s of capsid formation were sigmoidal, where the rate of the fast phase had second-power concentration dependence. The extent of assembly had third-pow er concentration dependence. Simulations based on the models recapitulated the concentration dependences observed for HBV capsid assembly. These resul ts strongly suggest that in vitro HBV assembly is nucleated by a trimer of dimers and proceeds by the addition of individual dimeric subunits. On the basis of this mechanism, we suggest that HBV capsid assembly could be an im portant target for antiviral therapeutics.