Protein stability promotes evolvability.
The biophysical properties that enable proteins to so readily evolve to perform diverse biochemical tasks are largely unknown. Here, we show that a protein's capacity to evolve is enhanced by the mutational robustness conferred by extra stability. We use simulations with model lattice proteins to demonstrate how extra stability increases evolvability by allowing a protein to accept a wider range of beneficial mutations while still folding to its native structure. We confirm this view experimentally by mutating marginally stable and thermostable variants of cytochrome P450 BM3. Mutants of the stabilized parent were more likely to exhibit new or improved functions. Only the stabilized P450 parent could tolerate the highly destabilizing mutations needed to confer novel activities such as hydroxylating the antiinflammatory drug naproxen. Our work establishes a crucial link between protein stability and evolution. We show that we can exploit this link to discover protein functions, and we suggest how natural evolution might do the same.
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA. jesse.bloom@gmail.com
Jesse D
JD
Bloom
Sy T
ST
Labthavikul
Christopher R
CR
Otey
Frances H
FH
Arnold
D020029:Base Pairing; D001483:Base Sequence; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017931:DNA Primers; D019143:Evolution, Molecular; D016368:Frameshift Mutation; D007700:Kinetics; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry / Q000235:genetics*; D013816:Thermodynamics
D017931:DNA Primers; D011506:Proteins; D003577:Cytochrome P-450 Enzyme System