Date of Original Version

10-3-2012

Type

Article

PubMed ID

23062347

Rights Management

This is an Open Access article distributed under the terms of the Creative Commons-Attribution Noncommercial License , which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract or Description

Virus capsid assembly has attracted considerable interest from the biophysical modeling community as a model system for complicated self-assembly processes. Simulation methods have proven valuable for characterizing the space of possible kinetics and mechanisms of capsid assembly, but they have so far been able to say little about the assembly kinetics or pathways of any specific virus. It is not possible to directly measure the detailed interaction rates needed to parameterize a model, and there is only a limited amount of experimental evidence available to constrain possible pathways, with almost all of it gathered from in vitro studies of purified coat proteins. In prior work, we developed methods to address this problem by using simulation-based data-fitting to learn rate parameters consistent with both structure-based rule sets and experimental light-scattering data on bulk assembly progress in vitro. We have since improved these methods and extended them to fit simulation parameters to one or more experimental light-scattering curves. Here, we apply the improved data-fitting approach to three capsid systems-human papillomavirus (HPV), hepatitis B virus (HBV), and cowpea chlorotic mottle virus (CCMV)-to assess both the range of pathway types the methods can learn and the diversity of assembly strategies in use between these viruses. The resulting fits suggest three different in vitro assembly mechanisms for the three systems, with HPV capsids fitting a model of assembly via a nonnucleation-limited pathway of accumulation of individual capsomers while HBV and CCMV capsids fit similar but subtly different models of nucleation-limited assembly through ensembles of pathways involving trimer-of-dimer intermediates. The results demonstrate the ability of such data fitting to learn very different pathway types and show some of the versatility of pathways that may exist across real viruses.

DOI

10.1016/j.bpj.2012.08.057

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Published In

Biophysical journal, 103, 7, 1545-1554.