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PEDS Advance Access published online on March 28, 2008
Protein Engineering Design and Selection, doi:10.1093/protein/gzn007
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Amino acid alphabet size in protein evolution experiments: better to search a small library thoroughly or a large library sparsely?

Enrique Muñoz1,2 and Michael W. Deem1,2,3

1Departments of Bioengineering 2Physics and Astronomy, Rice University, Houston, TX 77005–1892, USA

3 To whom correspondence should be addressed. E-mail: mwdeem{at}rice.edu

We compare the results obtained from searching a smaller library thoroughly versus searching a more diverse, larger library sparsely. We study protein evolution with reduced amino acid alphabets, by simulating directed evolution experiments at three different alphabet sizes: 20, 5 and 2. We employ a physical model for evolution, the generalized NK model, that has proved successful in modeling protein evolution, antibody evolution and T-cell selection. We find that antibodies with higher affinity are found by searching a library with a larger alphabet sparsely than by searching a smaller library thoroughly, even with well-designed reduced libraries. We also find ranked amino acid usage frequencies in agreement with observations of the CDR-H3 variable region of human antibodies.

Keywords: antibody engineering/directed evolution/generalized NK model/protein engineering/reduced amino acid code

Received January 25, 2008; revised January 25, 2008; accepted February 11, 2008.


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