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Synopses of Research Articles A Smart Mutation Scheme Produces Hundreds of Functional Proteins Richard Robinson | DOI: 10.1371/journal.pbio.0040136 A protein’s structure dictates its function, and one of the most direct and powerful ways to explore a proteins. Detailed analysis revealed the contribution to catalytic activity of a previously unappreciated amino acid near the enzyme’s active site. Some of the mutants were more resistant to heat degradation than the originals, indicating the potential for creating novel and possibly useful new variants using this method. The mutation method used here increased the yield of properly folded cytochromes by 10,000-fold over entirely random mutation techniques, and in one fell swoop nearly doubled the number of extant functional cytochromes P450. The results of this study will be useful for further structural analysis of the cytochrome P450 family, and the SCHEMA method for generating structurally intact mutants is likely to be applied to other protein families as well, both to tease out their structural secrets and perhaps to generate proteins with new properties that could be exploited for commercial or medical applications. protein’s function is by modifying its structure. Such an exploration is carried out naturally every time a protein’s gene is mutated, and the same process can be mimicked in the lab. Unfortunately, approaches that introduce random mutations frequently disrupt the interactions that keep a protein properly folded, rendering the mutant entirely functionless and the experimental results largely uninformative about the contributions made by speci?c amino acids to overall function. In a new study, Christopher Otey, Frances Arnold, and colleagues use recombination guided by structural modeling to ef?ciently generate a family of thousands of properly folded mutants of a protein, and reveal previously unknown in?uences on the protein’s function. DOI: 10.1371/journal.pbio.0040136.g001 The creation of an ar