Computational design of chimeric protein libraries for directed evolution.
The best approach for creating libraries of functional proteins with large numbers of nondisruptive amino acid substitutions is protein recombination, in which structurally related polypeptides are swapped among homologous proteins. Unfortunately, as more distantly related proteins are recombined, the fraction of variants having a disrupted structure increases. One way to enrich the fraction of folded and potentially interesting chimeras in these libraries is to use computational algorithms to anticipate which structural elements can be swapped without disturbing the integrity of a protein's structure. Herein, we describe how the algorithm Schema uses the sequences and structures of the parent proteins recombined to predict the structural disruption of chimeras, and we outline how dynamic programming can be used to find libraries with a range of amino acid substitution levels that are enriched in variants with low Schema disruption.
Silberg
Jonathan J
JJ
Cellzome AG, Heidelberg, Germany.
Nguyen
Peter Q
PQ
Stevenson
Taylor
T
D000465:Algorithms; D019943:Amino Acid Substitution; D002138:Calibration; D019295:Computational Biology / Q000379:methods*; D019020:Directed Molecular Evolution / Q000379:methods*; D006801:Humans; D019151:Peptide Library; D011994:Recombinant Proteins / Q000737:chemistry*
D019151:Peptide Library; D011994:Recombinant Proteins