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The computational algorithm SCHEMA was developed to estimate the disruption caused when amino acid residues that interact in the three‐dimensional structure of a protein are inherited from different parents upon recombination. To evaluate how well SCHEMA predicts disruption, we have shuffled the distantly‐related β‐lactamases PSE‐4 and TEM‐1 at 13 sites to create a library of 2¹⁴ (16,384) chimeras and examined which ones retain lactamase function. Sequencing the genes from ampicillin‐selected clones revealed that the percentage of functional clones decreased exponentially with increasing calculated disruption (E = the number of residue–residue contacts that are broken upon recombination). We also found that chimeras with low E have a higher probability of maintaining lactamase function than chimeras with the same effective level of mutation but chosen at random from the library. Thus, the …