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PEDS Advance Access published online on October 28, 2008
Protein Engineering Design and Selection, doi:10.1093/protein/gzn059
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Short Communication

Sequence determinants of protein aggregation in human VH domains

Kip Dudgeon1,3, Kristoffer Famm2,3 and Daniel Christ1,4

1Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia 2Centre for Protein Engineering, Medical Research Council Centre, Hills Road, Cambridge CB2 2QH, UK

4 To whom correspondence should be addressed. E-mail: d.christ{at}garvan.org.au

Human antibody variable heavy (VH) domains tend to aggregate upon denaturation, for instance, by heat or acid. We have previously demonstrated that domains resisting protein aggregation can be selected from CDR-only repertoires by phage display. Here we analysed their sequences to identify determinants governing protein aggregation. We found that, while many different CDR sequences conferred aggregation–resistance, certain physico-chemical properties were strongly selected for. Thus, hydrophobicity and beta-sheet propensity were significantly lower among the selected domains, whereas net negative charge was increased. Our results provide guidelines for the design of human VH repertoires with reduced levels of protein aggregation.

Keywords: antibodies/combinatorial repertoire/molecular evolution/phage display/protein aggregation

Received September 30, 2008; revised September 30, 2008; accepted October 6, 2008.

3 Both authors contributed equally to this work


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