SCHEMA Computational Design of Virus Capsid Chimeras: Calibrating How Genome Packaging, Protection, and Transduction Correlate with Calculated Structural Disruption

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dc.citation.firstpage724
dc.citation.issueNumber12
dc.citation.journalTitleACS Synthetic Biology
dc.citation.lastpage733
dc.citation.volumeNumber2
dc.contributor.authorHo, Michelle L.
dc.contributor.authorAdler, Benjamin A.
dc.contributor.authorTorre, Michael L.
dc.contributor.authorSilberg, Jonathan J.
dc.contributor.authorSuh, Junghae
dc.date.accessioned2017-08-04T12:30:01Z
dc.date.available2017-08-04T12:30:01Z
dc.date.issued2013
dc.description.abstractAdeno-associated virus (AAV) recombination can result in chimeric capsid protein subunits whose ability to assemble into an oligomeric capsid, package a genome, and transduce cells depends on the inheritance of sequence from different AAV parents. To develop quantitative design principles for guiding site-directed recombination of AAV capsids, we have examined how capsid structural perturbations predicted by the SCHEMA algorithm correlate with experimental measurements of disruption in seventeen chimeric capsid proteins. In our small chimera population, created by recombining AAV serotypes 2 and 4, we found that protection of viral genomes and cellular transduction were inversely related to calculated disruption of the capsid structure. Interestingly, however, we did not observe a correlation between genome packaging and calculated structural disruption; a majority of the chimeric capsid proteins formed at least partially assembled capsids and more than half packaged genomes, including those with the highest SCHEMA disruption. These results suggest that the sequence space accessed by recombination of divergent AAV serotypes is rich in capsid chimeras that assemble into 60-mer capsids and package viral genomes. Overall, the SCHEMA algorithm may be useful for delineating quantitative design principles to guide the creation of libraries enriched in genome-protecting virus nanoparticles that can effectively transduce cells. Such improvements to the virus design process may help advance not only gene therapy applications but also other bionanotechnologies dependent upon the development of viruses with new sequences and functions.
dc.identifier.citationHo, Michelle L., Adler, Benjamin A., Torre, Michael L., et al.. "SCHEMA Computational Design of Virus Capsid Chimeras: Calibrating How Genome Packaging, Protection, and Transduction Correlate with Calculated Structural Disruption." <i>ACS Synthetic Biology,</i> 2, no. 12 (2013) American Chemical Society: 724-733. https://doi.org/10.1021/sb400076r.
dc.identifier.digitalSCHEMA_computational_design_virus_capsid_chimeras
dc.identifier.doihttps://doi.org/10.1021/sb400076r
dc.identifier.urihttps://hdl.handle.net/1911/96590
dc.language.isoeng
dc.publisherAmerican Chemical Society
dc.rightsThis is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by the American Chemical Society.
dc.subject.keywordadeno-associated virus
dc.subject.keywordcapsid
dc.subject.keywordchimera
dc.subject.keywordprotein engineering
dc.subject.keywordrecombination
dc.subject.keywordSCHEMA
dc.titleSCHEMA Computational Design of Virus Capsid Chimeras: Calibrating How Genome Packaging, Protection, and Transduction Correlate with Calculated Structural Disruption
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpost-print
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