Quantum mechanical study of the conformational behavior of proline and 4R-hydroxyproline dipeptide analogues in vacuum and in aqueous solution

The conformational behavior of the title compds. has been investigated by Hartree-Fock, MP2, and DFT computations on the most significant structures related to variations of the backbone dihedral angles, cis/trans isomerism around the peptide bond, and diastereoisomeric puckering of the pyrrolidine ring. In vacuum the reversed g turn (g1), characterized by an intramol. hydrogen bridge, corresponds to the abs. energy min. for both puckerings (up and down) of the pyrrolidine ring. An addnl. energy min. is found in the helix region, but only for an up puckering of the pyrrolidine ring. When solvent effects are included by means of the polarizable continuum model the conformer obsd. exptl. in condensed phases becomes the abs. min. The down puckering is always favored over its up counterpart, albeit by different amts. (0.4-0.5 kcal/mol for helical structures and about 2 kcal/mol for g1 structures). In helical structures cis arrangements of the peptide bond are only slightly less stable than their trans counterparts. This is no longer true for g1 structures, because the formation of an intramol. hydrogen bond is possible only for trans peptide bonds. In most cases, proline and hydroxyproline show the same general trends; however, the electroneg. 4(R) substituent of hydroxyproline leads to a strong preference for up puckerings irresp. of the backbone conformation.