Simple Rules for Efficient Assembly Predict the Layout of a Packaged Viral RNA

Single-stranded RNA (ssRNA) viruses, which include major human pathogens, package their genomes as they assemble their capsids. We show here that the organization of the viral genomes within the capsids provides intriguing insights into the highly cooperative nature of the assembly process. A recent cryo-electron microscopy structure of bacteriophage MS2, determined with only 5-fold symmetry averaging, has revealed the asymmetric distribution of its encapsidated genome. Here we show that this RNA distribution is consistent with an assembly mechanism that follows two simple rules derived from experiment: (1) the binding of the MS2 maturation protein to the RNA constrains its conformation into a loop, and (2) the capsid must be built in an energetically favorable way. These results provide a new level of insight into the factors that drive efficient assembly of ssRNA viruses in vivo.

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► A mathematical model predicts the genome organization inside an ssRNA virus.
► Over 40,500 RNA configurations could match the icosahedrally averaged cryo-electron microscopy data.
► Only 66 are consistent with the circularization of viral RNA by maturation protein.
► One of these corresponds to the most energetically favorable pathway for assembly.
► Comparison with the 5-fold-averaged reconstruction confirms these predictions.