Evaluating the Influence of Environment on Virus Capsid Assembly Pathways through Stochastic Simulation

Abstract

Understanding the unique biochemical and physical differences between typical in vitro experimental systems and the in vivo environment of a living cell is a question of great importance in building and interpreting reliable models of complex reaction systems. Virus capsids make an excellent model system for such questions because they tend to have few components, making them amenable to in vitro and modeling studies, yet their assembly can be described by enormously complex networks of possible reactions that cannot be resolved by any current experimental technology. We have previously attempted to bridge the gap between the complexity of the system and the limitations of data for tracking detailed assembly pathways using simulation-based model inference, learning kinetic parameters of coarse-grained rule models by fitting simulations to light scattering data from in vitro capsid assembly systems. Here, we describe extensions of that work to attempt to understand the influence of specific features of the cellular environment, individually or in concert, on assembly pathway selection. We specifically focus on the effects of macromolecular crowding and nucleic acid on capsid assembly, using coarse-grained biophysical models to adjust rate parameters learned from the in vitro system and suggest how these adjustments to fine-scale interactions may alter high-level pathway selection. Results from a series of virus capsid models suggest surprisingly complex and often counterintuitive mechanisms by which crowding or nucleic acids can alternately promote or inhibit assembly for different virus and assembly conditions.