Conformational analysis of thiopeptides: (ϕ,ψ) maps of thio‐substituted dipeptides

Noncoded amino acids such as isobutyric acid have been used extensively in the process of drug design and protein engineering. This article focuses on a noncoded amino acid where the oxygen in the peptide unit is replaced with a sp 2 sulfur. It was hypothesized that the conformational space as well as the conformational preferences of thiopeptides will be more restricted and altered by the bulkier atom with different electrostatic properties. In vacuo conformational minima as well as associated energies for the thio‐substituted alanine dipeptides were calculated at the ab initio HF/6‐31G* level. When the bulkier sulfur atom acts as a hydrogen bond acceptor in the C 5 conformation or in the C \documentclass{article}\pagestyle{empty}\begin{document}$^{\mathrm{axial}}_{7}$\end{document} and C \documentclass{article}\pagestyle{empty}\begin{document}$^{\mathrm{equatorial}}_{7}$\end{document} conformations, the hydrogen bond lengths are much longer than that of normal peptides. Consequently, the ϕ, ψ dihedral angles of the C 5 , C \documentclass{article}\pagestyle{empty}\begin{document}$^{\mathrm{axial}}_{7}$\end{document} , and C \documentclass{article}\pagestyle{empty}\begin{document}$^{\mathrm{equatorial}}_{7}$\end{document} conformations change to accommodate the longer hydrogen bonds. The thiopeptide group is a poorer hydrogen bond acceptor and a better hydrogen bond donor than the normal peptide group. Therefore, thio‐substitution at the amino terminal leads to disfavoring of the C 7 conformations relative to the C 5 conformations and thio‐substitution at the carboxyl terminal leads to favoring of the C 7 conformations relative to the C 5 conformation. To simulate the conformations in solution, (ϕ,ψ) conformational energy maps were calculated for the glycine and alanine dipeptides at various dielectric constants using the CFF91 force field with our previously derived parameters for the thioamide group. The results show that thio‐substitution does restrict the conformations available to amino acids residues in peptides. Thio substitution at the amino terminal introduces unfavorable interactions near ϕ=−120 and 120, where there are increased overlaps between S n −1 H β , and S n −1 C β atoms, respectively. Thio substitution at the carboxyl terminal restricts the conformations near ψ=60, −60, and 180, which correspond with increase overlaps between S n C β , S n H β ′ and S n N n atoms, respectively. The effects of dithio substitutions of either the alanine or the glycine dipeptides are similar to the combined effects of the two single thio substitutions. © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 1026–1037, 2001