Puckering transition of the proline residue along the pseudorotational path: revisited

Abstract

Puckering transitions of the proline residue for Ac-Pro-X (X = OH, OMe, and NHMe) with trans and cis prolyl peptide bonds were explored along the pseudorotation phase angle using DFT methods in the gas phase and in water. It is observed that the puckering transition proceeds from a down-puckered conformation to an up-puckered one and vice versa through the transition state (TS) with an envelope form having the N atom on top of the envelope structure, although there are some differences in barriers to the puckering transition depending on the C-terminal end group. The relative conformational energies of local minima and TSs for Ac-Pro-X at the CCSD(T), MP2, M06-2X, and DSD-PBEP86-D3BJ levels of theory with various basis sets were assessed against the benchmark CCSD(T)/CBS-limit energies in the gas phase and in water. The double-hybrid DSD-PBEP86-D3BJ/def2-QZVP level of theory exhibited the best performance (RMSD ≈ 0.17 kcal mol⁻¹) against the benchmark CCSD(T)/CBS-limit energies. At all three levels of theory, the barrier height to the down-to-up puckering transition was in the order Ac-trans-Pro-OMe > Ac-trans-Pro-OH > Ac-trans-Pro-NHMe, whereas it was Ac-cis-Pro-NHMe > Ac-cis-Pro-OMe > Ac-cis-Pro-OH in water. From the comparison of the relative free energies of puckered structures and barriers to the puckering transition for Ac-trans-X-OMe (X = 11 C^γ-substituted Pro derivatives) in water, flp and mep residues exhibited a higher preference for down-puckering; and Hyp, Flp, and Mep residues exhibited a higher preference for up-puckering. Hence, the placement of flp/mep and Hyp/Flp/Mep in the X and Y positions of the X–Y-Gly triplet repeat in collagen model peptides, respectively, is expected to enhance the preorganization and thereby the stability of collagen triple helices.