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Abstract

The diversity of modern proteins arose through the combinatorial shuffling and differentiation of a limited number of autonomously folding domain prototypes, but the origin of these prototypes themselves has long remained poorly understood. In recent years, the proposal that they originated by repetition, accretion, and recombination from an ancestral set of peptides, which evolved as cofactors of RNA-based replication and catalysis, has gained wide acceptance, supported by the systematic identification of such ancestral peptides and the experimental recapitulation of the mechanisms by which they could have yielded the first folded proteins. Inspired by this evolutionary process, protein engineers have seized on design from pre-optimized peptide components as a powerful approach to generating proteins with novel topology and functionality.