The Crystal Structural Foundation of the “Rippled” Beta‐Sheet

ABSTRACT The “rippled” β‐sheet was theorized by Pauling and Corey in 1953, yet, unlike the pleated β‐sheet, remained obscure for well over half a century. From 2011 onward, the studies conducted independently by the Schneider, Nilsson and Raskatov laboratories provided the critical nucleus of biophysical data to support the viability of the rippled sheet, stimulating the ensuing x‐ray structural work. The first rippled sheet crystal structure was reported by us in 2022, 69 years after its prediction. The field has since witnessed a rapid expansion in terms of both crystal structural understanding and conceptual innovation concerning novel motif types. We have reported fifteen rippled sheet crystal structures thus far. Of the 20 canonical amino acids, our published studies have established 13 to be ripple‐genic, that is, capable of forming rippled sheets. Reported ripple‐genic systems range from tri‐ to heptapeptide in length. Among the newest advances are the mixed chirality motifs, capable of forming rippled sheets from single components, as well as conformationally locked rippled sheet macrocycles. The maturing crystal structural foundation is expected to stimulate many new and interesting applications including biomaterials, as well as molecular recognition of intrinsically disordered proteins and peptides.