Conformational Preferences of X-Pro Sequences: Ala-Pro and Aib-Pro Motifs

• Published in: The journal of physical chemistry. B Vol. 114; no. 44; pp. 14077 - 14086
• Main Authors: Byun, Byung Jin, Song, Il Keun, Chung, Yong Je, Ryu, Keun Ho, Kang, Young Kee
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 11.11.2010
• Subjects: Amino Acid Motifs; B: Biophysical Chemistry; Crystallography, X-Ray; Dipeptides - chemistry; Gases - chemistry; Models, Molecular; Protein Conformation; Quantum Theory; Stereoisomerism; Thermodynamics; Water - chemistry
• ISSN: 1520-6106; 1520-5207
• DOI: 10.1021/jp107200f

Conformational preferences and prolyl cis−trans isomerizations of the X-Pro motifs (Ac-X-Pro-NHMe, X = Ala and Aib) are explored using the meta-hybrid functional M06-2X and the double-hybrid functional B2PLYP-D with empirical dispersion corrections in the gas phase and in water, where solvation free energies were calculated using the implicit SMD model. Ac-Ala-Pro-NHMe favors the type VI β-turns in the gas phase and the open conformations in water. The populations of type VI β-turns decrease from 71% in the gas phase to 21% in water, which is reasonably consistent with IR and NMR experimental results on tBoc-Ala-Pro-NHMe. However, Ac-Aib-Pro-NHMe prefers the type I β-turns with α-helical structures for both residues in the gas phase and in water, whose populations are estimated to be 66% in both phases. These calculated results may rationalize why most of the peptaibiotics containing the Aib-Pro sequence have a regular α-helical conformation at the N- or C-terminus but a kinked α-helical structure in the middle of the helix. The cis−trans isomerizations of the Ala-Pro and Aib-Pro peptide bonds proceed via the clockwise rotation with the different backbone conformations. The rotational barriers to cis-to-trans isomerization are estimated to be 19.73 kcal/mol for the Ala-Pro tripeptide and 16.64 kcal/mol for the Aib-Pro tripeptide in water, which indicates that the rotational barrier becomes lower by ∼3 kcal/mol for the Aib-Pro peptide bond. The calculated rotational barrier for Ac-Ala-Pro-NHMe is consistent with the observed value of 19.3 kcal/mol for Suc-Ala-Ala-Pro-Phe-pNA from NMR experiments in a buffered solution.