A lone pair of the oxygen in peptide bonds is well known to accept a hydrogen bond in alpha-helices and beta-sheets. Using synthetic peptides, we have discovered that the other electron pair also participates in meaningful interactions in both of these structural elements. In an alpha-helix, this interaction is an O…C=O n-to-pi* interaction with the next carbonyl group in the main chain. In a beta-sheet, this interaction is an O…H–N hydrogen bond within the residue. Both of these interactions entail the formation of 5-membered rings and involve significant overlap of non-bonding and anti-bonding orbitals. Whereas the canonical hydrogen bonds engage the s orbital of the oxygen, the n-to-pi* interaction and “C5” hydrogen bond engage a p orbital that is orthogonal to the C=O bond. These latter interactions, which are enhanced by the orbital demixing that accompanies canonical hydrogen-bond formation, have measurable effects on peptide and protein structure.

Award Address (Ralph F. Hirschmann Award in Peptide Chemistry sponsored by Merck Research Laboratories). Unappreciated forces that stabilize peptides and proteins

251st National Meeting (2016)

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