Conformations of thioamide-containing dipeptides: A computational study

Four model dipeptides, Ac-psi[CSNH]-Gly-NHMe, Ac-Gly-psi[CSNH]-NHMe, Ac-psi[CSNH]-Ala-NHMe, and Ac-Ala-psi[CSNH]-NHMe, each containing a thioamide bond, were studied by high-level ab initio calculations. For each model compound, a conformational potential energy surface was generated by constrained optimization at the HF/6-31G*//HF/6-31G* level of 144 starting geometries, resulting from the systematic variation of the two flexible backbone torsions phi and psi. Selected regions of each potential energy surface were used as starting points for full geometry optimization at the HF/6-31G*//HF/6-31G* and MP2/6-31G*//MP2/6-31G* levels. The structures and energies of the resulting minima were used to examine the conformational behavior of the model compounds. Whereas the conformations of the C-terminal thioamides were generally close to those of the corresponding peptides, the N-terminal thioamides displayed markedly different conformational behavior. The changes in the conformational profile of thioamide-containing peptides appear to result from a combination of the decreased hydrogen bonding-accepting ability and increased size of sulfur versus oxygen and lengthening of the C=S bond in the thioamide as compared to the C=O bond in an amide. Insertion of a thioamide linkage into a peptide structure is thus not conformationally neutral and can produce substantial changes in peptide structure, primarily in the residues on the C-terminal side of the thioamide. In addition to the effects on the proteolysis of peptides, the results indicate that this substitution may demonstrate utility as a probe of local peptide secondary structure.