Multiscale Simulation of Nucleation-limited Viral Capsid Assembly

Viral capsids provide a striking example of the complexity and diversity in self-assembled biological systems. Computer simulations of capsids therefore serve as a valuable test bed for understanding and predicting the behavior of complicated macromolecular self-assembly in general. Previous work in our lab has focused on investigating pathway usage in model capsid assembly systems across broad parameter ranges primarily using models based on the stochastic simulation algorithm (SSA). The standard SSA, though, can become highly inefficient for multi-timescale problems, where important events occur in parallel and at a much slower rate than other relatively unimportant events. Recently, we have devised two new algorithms based on the spectral analysis of Continuous Time Markov Model (CTMM) graphs to accelerate sampling of rare events in SSA models. These methods are well suited for simulating a broad class of “stiff” reaction networks, including some important parameter domains for modeling self-assembly of nucleation-limited systems. We demonstrate these methods for use in modeling nucleation events and multi-bond dissociation events, important issues in accurately modeling capsid-like assembly near the critical concentration. We are now applying these methods to develop more accurate and efficient models of capsid assembly at low (in vitro) concentrations.