Nature Biotechnology 1995 August, 13:722-723

Searching Sequence Space

Douglas C. Youvan

Excerpts from a Correpondence to Nature Biotechnology

To the editor:

In an article¹ by this same title, Willem Stemmer of the Affymax Research Institute has made a very good argument for using genetic algorithms (GAs) to search protein sequence space.

Which GA-based technology is best? That probably depends on the protein and the specific engineering goal.  One advantage of REM is its synergistic interaction with the structure of the genetic code^4,5,8,16 having to do with hydropathy and molar volume, important determinants of protein structure and function.  The "highly impractical,¹" labor intensive aspects of EEM are lessened by new PCR methodology,¹⁷ laboratory automation, and high throughput screening.  However, given the fact that the field of combinatorial chemistry is still in its infancy, it is probably wise to consider all of the proven mutagenesis methods: GA-PCR, REM, and its relatives, error-prone PCR, parsimonious mutagenesis, and structurally guided or sequential random mutagenesis.¹⁹

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