The Role of Packaging Sites in Efficient and Specific Virus Assembly

During the life cycle of many single-stranded RNA viruses, including many human pathogens, a protein shell called the capsid spontaneously assembles around the viral genome. Understanding the mechanisms by which capsid proteins selectively assemble around the viral RNA amidst diverse host RNAs is a key question in virology. In one proposed mechanism, short sequences (packaging sites) within the genomic RNA promote rapid and efficient assembly through specific interactions with the capsid proteins. In this work, we develop a coarse-grained particle-based computational model for capsid proteins and RNA that represents protein-RNA interactions arising both from nonspecific electrostatics and from specific packaging site interactions. Using Brownian dynamics simulations, we explore how the efficiency and specificity of assembly depend on solution conditions (which control protein-protein and nonspecific protein-RNA interactions) and the strength and number of packaging sites. We identify distinct regions in parameter space in which packaging sites lead to highly specific assembly via different mechanisms and others in which packaging sites lead to kinetic traps. We relate these computational predictions to in vitro assays for specificity in which cognate viral RNAs compete against non-cognate RNAs for assembly by capsid proteins.