Premium
Computationally Mapping Sequence Space To Understand Evolutionary Protein Engineering
Author(s) -
Armstrong Kathryn A.,
Tidor Bruce
Publication year - 2008
Publication title -
biotechnology progress
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.572
H-Index - 129
eISSN - 1520-6033
pISSN - 8756-7938
DOI - 10.1021/bp070134h
Subject(s) - sequence space , sequence (biology) , protein engineering , computational biology , computer science , directed evolution , directed molecular evolution , evolutionary algorithm , space (punctuation) , stability (learning theory) , protein sequencing , biology , genetics , machine learning , peptide sequence , mathematics , gene , mutant , biochemistry , pure mathematics , banach space , enzyme , operating system
Evolutionary protein engineering has been dramatically successful, producing a wide variety of new proteins with altered stability, binding affinity, and enzymatic activity. However, the success of such procedures is often unreliable, and the impact of the choice of protein, engineering goal, and evolutionary procedure is not well understood. We have created a framework for understanding aspects of the protein engineering process by computationally mapping regions of feasible sequence space for three small proteins using structure‐based design protocols. We then tested the ability of different evolutionary search strategies to explore these sequence spaces. The results point to a non‐intuitive relationship between the error‐prone PCR mutation rate and the number of rounds of replication. The evolutionary relationships among feasible sequences reveal hub‐like sequences that serve as particularly fruitful starting sequences for evolutionary search. Moreover, genetic recombination procedures were examined, and tradeoffs relating sequence diversity and search efficiency were identified. This framework allows us to consider the impact of protein structure on the allowed sequence space and therefore on the challenges that each protein presents to error‐prone PCR and genetic recombination procedures.