Non-covalent interactions play a key role in biomolecular phenomena such as the stabilization of protein tertiary and quaternary structure or protein-protein and protein-substrate recognition. Among these interactions, the classical amide-type NH→O=C hydrogen bond has been thoroughly studied. The study of other types of non-covalent interactions implicating peptide backbone NH groups is much rarer. This presentation focuses on the role of NH→S hydrogen bonding in determining the conformational preferences of thioether amino acid residues and their short oligomers. A panel of capped derivatives of non-canonical sulfur-containing amino acids - Cys(Me) (acyclic), Attc (thietane), Atlc (thiolane), Atc (thiane) - have been characterized computationally, in the gas phase, in solution, and in some cases in the solid state. We have discovered the co-existence of C6γ NH→S hydrogen bonds and C5 NH→O=C interactions in each of these four compounds. This combined stabilizing feature was also prevalent in an Attc dimer and trimer. An intra-residue C5γ NH→S hydrogen bond is in evidence in short oligomers of Atlc and Atc. The significance of NH→S bonding in the combined C6γ–C5 structural feature of Attc was evaluated by comparison with capped derivatives of other four-membered ring amino acids: Ac4c (cyclobutane), Aatc(Me) (azetidine), Aotc (oxetane). The C5–C6γ interaction is present in the three heterocyclic residues, with increasing strength of NH→X hydrogen bonding from X=O to X=S to X=N.

Short range NH→S interactions in peptide models

ACS Fall 2021

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