The Rippled Beta-Sheet: An Old Prediction Inspires a New Field.

The rippled β-sheet was predicted by Linus Pauling and Robert Corey in 1953. Unlike the closely related pleated β-sheet, which rapidly expanded to become common textbook knowledge, the rippled β-sheet remained obscure for decades. The critical body of biophysical evidence for the structural viability of this neglected motif only began to emerge in the 2000s and onwards. The first crystal structure of a rippled β-sheet was reported by our laboratory in 2022, that is, 69 years since its original prediction. From model tripeptides, we gradually expanded to longer, biologically relevant sequences. Subsequent rational molecular design led to the creation of chimeric mixed chirality peptides capable of forming rippled sheets from single components (i.e., "self-rippling" peptides), as well as rippled sheet macrocycles. Over half of the canonical amino acid alphabet has meanwhile been observed in the context of the rippled β-sheet. The number of ripple-genic amino acids keeps expanding as the field continues to mature. The rippled β-sheet is a platform that allows readily accessing a wide variety of aggregated peptidic folds, often with unique properties. The field is wide open for discovery.