Journal
ACS SYNTHETIC BIOLOGY
Volume 2, Issue 12, Pages 724-733Publisher
AMER CHEMICAL SOC
DOI: 10.1021/sb400076r
Keywords
adeno-associated virus; capsid; chimera; protein engineering; recombination; SCHEMA
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Funding
- Keck Center of the Gulf Coast Consortia Nanobiology Interdisciplinary Graduate Training Program (National Institute of Biomedical Imaging and Bioengineering Grant) [T32EB009379]
- Robert A. Welch Foundation [C-1614]
- National Science Foundation [1150138]
- National Science Foundation Research Experiences for Undergraduates [1004853]
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [1150138] Funding Source: National Science Foundation
- Div Of Biological Infrastructure
- Direct For Biological Sciences [1004853] Funding Source: National Science Foundation
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Adeno-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.
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