Conformational preferences of the 2-methylproline residue and its role in stabilizing β-turn and polyproline II structures of peptides

Abstract

Conformational preferences of the 2-methylproline (2-MePro) residue and its role in stabilizing β-turn and polyproline II (PII) structures of peptides have been studied using density functional methods in the gas phase and in water. The population of the C7 H-bonded structures of Ac-2-MePro-NHMe is calculated to be dominant in the gas phase, whereas they become significantly depopulated and the populations of polyproline and α-helical structures increase in water. Due to the increased stability of the up-puckered PII structure, the populations of its PII and PI structures are more increased by 10.9% and decreased by 12.2% than Ac-Pro-NHMe in water, respectively. There is a large decrease in the cis population by 20.6% for the prolyl peptide bond by replacing Pro with 2-MePro in water, which is consistent with 13C NMR experiments. For Ac-Ala-2-MePro-NHMe, the conformer with a βI-turn is found to be the most preferred conformer with the population of 25.2% in water, whereas the open conformers are dominantly populated for Ac-Ala-Pro-NHMe. This is consistent with experimental results that the Ala-Pro sequence of the antigen mimotope associated with autoimmune recurrent thrombosis has been known to adopt a stable βI-turn structure with the replacement of Pro by 2-MePro in water. With the replacement of a single Pro by 2-MePro in the middle of the sequences of the polyproline model peptide Ac-(Pro)5-NMe2 and the single-strand model peptide of collagen Ac-(Hyp-Gly-Pro)2-NMe2, the relative stabilities of the PII structures are enhanced by 8.11 and 3.91 kcal mol−1, respectively, although there are only small changes in backbone torsion angles of both PII and PI structures. It can be deduced that the single strands of (Hyp-Gly-2-MePro)n with the stable PII structure might provide more stability to their triple helix.