Design Guidelines to Control Rippled β-Sheets versus Pleated β-Sheets in Mixed-Chirality Peptides

Decoding how amino acid sequences determine structure facilitates the design of functional proteins, advanced biomaterials, and selective, low-side-effect drugs. The rippled β-sheet, theorized by Pauling and Corey in 1953, has only recently begun to gain experimental support. However, research on rippled β-sheets remains limited, leaving gaps in our understanding of when and how they occur. To understand the relationship between sequences and rippled β-sheet formation propensities, we carried out molecular dynamics (MD) and density functional theory (DFT) simulations to predict the energetics for six systems of forming either a rippled or pleated β-sheets that are ordered either parallel or antiparallel. Notably, among these four possible structures of each system, the structure predicted to have the lowest energy agrees with the single case observed experimentally! To understand why this form is favored, we investigate the local structures of all six systems, with particular attention to the role of hydrogen bonds (H-bonds) in stabilization. In each system, the peptide consistently adopts a motif that allows it to form the maximum number of H-bonds between backbones, even when amidated, and composed of a single-component with mixed chirality or a cyclic peptide. We find that an achiral glycine–glycine bridge acts as a spacer between valine residues, effectively reducing steric hindrance between side chains. Furthermore, we conclude that the structures of cyclic peptides are stabilized by intramolecular H-bonds in an anhydrous environment. Our findings provide deeper insights into how sequences influence β-sheet conformations, enabling us to propose guidelines for the preferred structures of novel peptides.