Natural proteins are the result of billions of years of evolution. The earliest predecessors of today's proteins are believed to have emerged from random polypeptides. While we have no means to determine how this process exactly happened, there is great interest in understanding how it reasonably could have happened. We are reviewing how researchers have utilized in vitro selection and molecular evolution methods to investigate plausible scenarios for the emergence of early functional proteins. The studies range from analyzing general properties and structural features of unevolved random polypeptides to isolating de novo proteins with specific functions from synthetic randomized sequence libraries or generating novel proteins by combining evolution with rational design. While the results are exciting, more work is needed to fully unravel the mechanisms that seeded protein-dominated biology.
Bibliographical noteFunding Information:
We thank Stephen P. Miller and Romas J. Kazlauskas for critical reading of the manuscript. We gratefully acknowledge financial support from the US National Aeronautics and Space Administration (NASA) 80NSSC18K1277 , the US National Institutes of Health (NIH) ( GM108703 ), Human Frontier Science Program ( RGP0041 ), and the Simons Collaboration on the Origins of Life ( 340762 ).
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