The supramolecular chemistry of β-sheets

Interactions among β-sheets occur widely in protein quaternary structure, protein-protein interaction, and protein aggregation and are central in Alzheimer's and other amyloid-related diseases. This Perspective looks at the structural biology of these important yet under-appreciated interactions from a supramolecular chemist's point of view. Common themes in the supramolecular interactions of β-sheets are identified and richly illustrated though examples from proteins, amyloids, and chemical model systems. β-Sheets interact through edge-to-edge hydrogen bonding to form extended layers and through face-to-face hydrophobic or van der Waals interactions to form layered sandwich-like structures. Side chains from adjacent layers can fit together through simple hydrophobic contacts or can participate in complementary interdigitation or knob-hole interactions. The layers can be aligned, offset, or rotated. The right-handed twist of β-sheets provides additional opportunities for stabilization of edge-to-edge contacts and rotated layered structures.