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Why reinvent the wheel? Building new proteins based on ready‐made parts
Author(s) -
Khersonsky Olga,
Fleishman Sarel J.
Publication year - 2016
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1002/pro.2892
Subject(s) - protein design , repertoire , protein engineering , computer science , synthetic biology , fragment (logic) , point (geometry) , counterpoint , natural (archaeology) , protein structure , computational biology , biology , programming language , physics , biochemistry , paleontology , geometry , mathematics , acoustics , enzyme
Abstract We protein engineers are ambivalent about evolution: on the one hand, evolution inspires us with myriad examples of biomolecular binders, sensors, and catalysts; on the other hand, these examples are seldom well‐adapted to the engineering tasks we have in mind. Protein engineers have therefore modified natural proteins by point substitutions and fragment exchanges in an effort to generate new functions. A counterpoint to such design efforts, which is being pursued now with greater success, is to completely eschew the starting materials provided by nature and to design new protein functions from scratch by using de novo molecular modeling and design. While important progress has been made in both directions, some areas of protein design are still beyond reach. To this end, we advocate a synthesis of these two strategies: by using design calculations to both recombine and optimize fragments from natural proteins, we can build stable and as of yet un‐sampled structures, thereby granting access to an expanded repertoire of conformations and desired functions. We propose that future methods that combine phylogenetic analysis, structure and sequence bioinformatics, and atomistic modeling may well succeed where any one of these approaches has failed on its own.