The borderlands of foldability: lessons from simplified proteins

Abstract

Proteins make complex life possible, yet our understanding of their emergence remains limited. What are the informational limits of protein folding, and how did the first proteins emerge? Protein simplification studies—in which contemporary folds are built from limited alphabets, symmetrized, fragmented, or shortened—have provided key insights into these questions. These studies use design constraints to address the discoverability of, and connectedness between, protein folds. By considering various environments, such as high salt concentrations or peptide–nucleic acid coacervates, the role of context in the emergence of folded domains is explored. Taken together, these studies support the early emergence of protein folds and reveal the existence of highly connected and readily traversable regions of sequence–structure space.