Dataset Information

Stochastic dynamics of virus capsid formation: direct versus hierarchical self-assembly.

ABSTRACT:

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Background

In order to replicate within their cellular host, many viruses have developed self-assembly strategies for their capsids which are sufficiently robust as to be reconstituted in vitro. Mathematical models for virus self-assembly usually assume that the bonds leading to cluster formation have constant reactivity over the time course of assembly (direct assembly). In some cases, however, binding sites between the capsomers have been reported to be activated during the self-assembly process (hierarchical assembly).

Results

In order to study possible advantages of such hierarchical schemes for icosahedral virus capsid assembly, we use Brownian dynamics simulations of a patchy particle model that allows us to switch binding sites on and off during assembly. For T1 viruses, we implement a hierarchical assembly scheme where inter-capsomer bonds become active only if a complete pentamer has been assembled. We find direct assembly to be favorable for reversible bonds allowing for repeated structural reorganizations, while hierarchical assembly is favorable for strong bonds with small dissociation rate, as this situation is less prone to kinetic trapping. However, at the same time it is more vulnerable to monomer starvation during the final phase. Increasing the number of initial monomers does have only a weak effect on these general features. The differences between the two assembly schemes become more pronounced for more complex virus geometries, as shown here for T3 viruses, which assemble through homogeneous pentamers and heterogeneous hexamers in the hierarchical scheme. In order to complement the simulations for this more complicated case, we introduce a master equation approach that agrees well with the simulation results.

Conclusions

Our analysis shows for which molecular parameters hierarchical assembly schemes can outperform direct ones and suggests that viruses with high bond stability might prefer hierarchical assembly schemes. These insights increase our physical understanding of an essential biological process, with many interesting potential applications in medicine and materials science.

SUBMITTER: Baschek JE

PROVIDER: S-EPMC3563543 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Publications

Stochastic dynamics of virus capsid formation: direct versus hierarchical self-assembly.

Baschek Johanna E JE R Klein Heinrich C HC Schwarz Ulrich S US

BMC biophysics 20121217

<h4>Unlabelled</h4><h4>Background</h4>In order to replicate within their cellular host, many viruses have developed self-assembly strategies for their capsids which are sufficiently robust as to be reconstituted in vitro. Mathematical models for virus self-assembly usually assume that the bonds leading to cluster formation have constant reactivity over the time course of assembly (direct assembly). In some cases, however, binding sites between the capsomers have been reported to be activated dur ...[more]

PMID: 23244740

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Project description:The HI loop is a prominent domain on the adeno-associated virus (AAV) capsid surface that extends from each viral protein (VP) subunit overlapping the neighboring fivefold VP. Despite the highly conserved nature of the residues at the fivefold pore, the HI loops surrounding this critical region vary significantly in amino acid sequence between the AAV serotypes. In order to understand the role of this unique capsid domain, we ablated side chain interactions between the HI loop and the underlying EF loop in the neighboring VP subunit by generating a collection of deletion, insertion, and substitution mutants. A mutant lacking the HI loop was unable to assemble particles, while a substitution mutant (10 glycine residues) assembled particles but was unable to package viral genomes. Substitution mutants carrying corresponding regions from AAV1, AAV4, AAV5, and AAV8 yielded (i) particles with titers and infectivity identical to those of AAV2 (AAV2 HI1 and HI8), (ii) particles with a decreased virus titer (1 log) but normal infectivity (HI4), and (iii) particles that synthesized VPs but were unable to assemble into intact capsids (HI5). AAV5 HI is shorter than all other HI loops by one amino acid. Replacing the missing residue (threonine) in AAV2 HI5 resulted in a moderate particle assembly rescue. In addition, we replaced the HI loop with peptides varying in length and amino acid sequence. This region tolerated seven-amino-acid peptide substitutions unless they spanned a conserved phenylalanine at amino acid position 661. Mutation of this highly conserved phenylalanine to a glycine resulted in a modest decrease in virus titer but a substantial decrease (1 log order) in infectivity. Subsequently, confocal studies revealed that AAV2 F661G is incapable of efficiently completing a key step in the infectious pathway nuclear entry, hinting at a possible perturbation of VP1 phospholipase activity. Molecular modeling studies with the F661G mutant suggest that disruption of interactions between F661 and an underlying P373 residue in the EF loop of the neighboring subunit might adversely affect incorporation of the VP1 subunit at the fivefold axis. Western blot analysis confirmed inefficient incorporation of VP1, as well as a proteolytically processed VP1 subunit that could account for the markedly reduced infectivity. In summary, our studies show that the HI loop, while flexible in amino acid sequence, is critical for AAV capsid assembly, proper VP1 subunit incorporation, and viral genome packaging, all of which implies a potential role for this unique surface domain in viral infectivity.

Dataset Information

Stochastic dynamics of virus capsid formation: direct versus hierarchical self-assembly.

Unlabelled

Background

Results

Conclusions

Publications

Stochastic dynamics of virus capsid formation: direct versus hierarchical self-assembly.

Similar Datasets

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