Conformational preferences and prolyl cis-trans isomerizations of the (2S,4S)-4-methylproline (4S-MePro) and (2S,4R)-4-methylproline (4R-MePro) residues are explored at the M06-2X/cc-pVTZ//M06-2X/6-31+G(d) level of theory in the gas phase and in water, where solvation free energies were calculated using the implicit SMD model. In the gas phase, the down-puckered γ-turn structure with the trans prolyl peptide bond is most preferred for both Ac-4S-MePro-NHMe and Ac-4R-MePro-NHMe, in which the C(7) hydrogen bond between two terminal groups seems to play a role, as found for Ac-Pro-NHMe. Because of the C(7) hydrogen bonds weakened by the favorable direct interactions between the backbone C==O and H--N groups and water molecules, the 4S-MePro residue has a strong preference of the up-puckered polyproline II (PP(II)) structure over the down-puckered PP(II) structure in water, whereas the latter somewhat prevails over the former for the 4R-MePro residue. However, these two structures are nearly equally populated for Ac-Pro-NHMe. The calculated populations for the backbone structures of Ac-4S-MePro-NHMe and Ac-4R-MePro-NHMe in water are reasonably consistent with CD and NMR experiments. In particular, our calculated results on the puckering preference of the 4S-MePro and 4R-MePro residues with the PP(II) structures are in accord with the observed results for the stability of the (X-Y-Gly)(7) triple helix with X = 4R-MePro or Pro and Y = 4S-MePro or Pro. The calculated rotational barriers indicate that the cis-trans isomerization may in common proceed through the anticlockwise rotation for Ac-4S-MePro-NHMe, Ac-4R-MePro-NHMe, and Ac-Pro-NHMe in water. The lowest rotational barriers become higher by 0.24-1.43 kcal/mol for Ac-4S-MePro-NHMe and Ac-4R-MePro-NHMe than those for Ac-Pro-NHMe in water.
2010 Wiley Periodicals, Inc.