Pathways for Virus Assembly around Nucleic Acids

• The spontaneous assembly of viral capsids is an essential step in the life cycle of many viruses and provides a paradigm for efficient, high-fidelity molecular self-assembly.
• Capsid assembly around a negatively charged substrate can proceed through two classes of pathways, depending upon the properties of the capsid proteins and solution conditions.
• We perform computer simulations predicting that these pathways can be distinguished using two different experimental techniques.
• Assembly pathways and their sensitivity to control parameters may be an important factor in determining the effectiveness of antiviral agents and engineered delivery vectors.

Understanding the pathways by which viral capsid proteins assemble around their genomes could identify key intermediates as potential drug targets. In this work, we use computer simulations to characterize assembly over a wide range of capsid protein–protein interaction strengths and solution ionic strengths. We find that assembly pathways can be categorized into two classes, in which intermediates are either predominantly ordered or disordered. Our results suggest that estimating the protein–protein and the protein–genome binding affinities may be sufficient to predict which pathway occurs. Furthermore, the calculated phase diagrams suggest that knowledge of the dominant assembly pathway and its relationship to control parameters could identify optimal strategies to thwart or redirect assembly to block infection. Finally, analysis of simulation trajectories suggests that the two classes of assembly pathways can be distinguished in single-molecule fluorescence correlation spectroscopy or bulk time-resolved small-angle X-ray scattering experiments.

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