cover illustration The directed laboratory evolution of antibodies constructed from reduced amino-acid alphabets of sizes of 2, 5, and 20 was simulated. The binding free energy of the antibody was evolved, starting from an initially modest level. The free energy of substrate binding decreased as the number of rounds of evolution increased. We found that antibodies constructed from the largest alphabet sizes were the most functional. That is, antibodies of 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 amino-acid alphabet libraries. This result is perhaps the reason for the diversity of amino acids found in nature and suggests a general motivation for the search to discover and incorporate unnatural amino acids in protein evolution experiments are described in the manuscript by Muñoz et al., 311-317.
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