Quantum mechanical origin of the conformational preferences of 4-thiaproline and its S-oxides

• Published in: Amino acids Vol. 41; no. 1; pp. 181 - 186
• Main Authors: Choudhary, Amit, Pua, Khian Hong, Raines, Ronald T
• Format: Journal Article
• Language: English
• Published: Vienna Vienna : Springer Vienna 01-06-2011; Springer Vienna; Springer Nature B.V
• Subjects: Amino acids; Analytical Chemistry; Architecture; Biochemical Engineering; Biochemistry; Biomedical and Life Sciences; Bonding; Crystallography, X-Ray; Esters; isomers; Life Sciences; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Neurobiology; NMR spectroscopy; nuclear magnetic resonance spectroscopy; Original Article; oxides; Oxides - chemistry; oxygen; Peptides; Proline; Proline - analogs & derivatives; Proline - chemistry; Proteomics; Quantum Theory; ringing; Rings (mathematics); Sulfur; X-ray diffraction; π interaction; Collagen; Stereoelectronic effect; Thiazolidine
• ISSN: 0939-4451; 1438-2199
• DOI: 10.1007/s00726-010-0504-8

The saturated ring and secondary amine of proline spawn equilibria between pyrrolidine ring puckers as well as peptide bond isomers. These conformational equilibria can be modulated by alterations to the chemical architecture of proline. For example, Cγ in the pyrrolidine ring can be replaced with sulfur, which can be oxidized either stereoselectively to yield diastereomeric S-oxides or completely to yield a sulfone. Here, the thiazolidine ring and peptide bond conformations of 4-thiaproline and its S-oxides were analyzed in an Ac-Xaa-OMe system using NMR spectroscopy, X-ray crystallography, and hybrid density functional theory. The results indicate that the ring pucker of the S-oxides is governed by the gauche effect, and the prolyl peptide bond conformation is determined by the strength of the n → π* interaction between the amide oxygen and the ester carbonyl group. These findings, which are consistent with those of isologous 4-hydroxyprolines and 4-fluoroprolines, substantiate the importance of electron delocalization in amino acid conformation.