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

Protein Eng Des Sel. 2008 May;21(5):311-7. doi: 10.1093/protein/gzn007. Epub 2008 Mar 28.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / chemistry*
  • Computer Simulation
  • Entropy
  • Evolution, Molecular
  • Gene Library
  • Models, Statistical
  • Monte Carlo Method
  • Peptide Library
  • Protein Conformation
  • Protein Engineering / methods*
  • Protein Structure, Tertiary
  • Proteins / chemistry*
  • Saccharomyces cerevisiae / metabolism
  • T-Lymphocytes / metabolism

Substances

  • Amino Acids
  • Peptide Library
  • Proteins