Flexibility of the pyrrolidine ring in proline peptides

Abstract

AbstractA survey of over 50 crystal structures indicates that both imino acid and peptide derivatives of proline populate ring conformers consistent with the torsional potentials about single bonds. In both cases, lower barriers for rotation about CN bonds relative to those about CC bonds favor smaller values for dihedral angles about the former bonds. In peptides a minimum in the torsional potential about CN bonds occurs at zero dihedral angle, further favoring small angles. The pyrrolidine‐ring dihedral angles of the proline compounds in the solid state obey a cyclopentane‐type pseudorotation function. Thus the puckering of the five‐membered ring can be quantitatively described by two parameters. Consistent with small dihedral angles about CN bonds, Cβ and/or Cγ are puckered out of the mean plane of the ring in nearly all of the nonstrained compounds.Utilizing the consistent force‐field method of Lifson and coworkers [see A. Warshel, M. Levitt, and S. Lifson (1970) J. Mol. Spectrosc. 33, 84] the intramolecular energy of five proline peptides was minimized with respect to all internal coordinates. In addition, the energy surface near minima was explored by constraining a particular dihedral angle and reminimizing the energy with respect to all remaining variables. In linear peptides two types of pyrrolidine‐ring conformers have identical predicted energies. In the cyclic dipeptide cyclo (Pro‐Gly) one of the ring conformers is favored by about 3 kcal/mol, while the cyclic tripeptide cyclo(Pro‐Gly‐Gly) favors the other conformer by a comparable margin. In agreement with observations in the solid state and in solution, Cβ and/or Cγ are puckered in the predicted conformers. A correlation between proline Φ and the details of the puckered conformation was predicted and found to match precisely conformers observed in crystals.For the diamides N‐acetyl‐L‐proline‐N′‐methyl‐amide and N‐acetyl‐L‐proline‐N′,N′‐dimethylamide (AcProMe2A) 30% and 60% cis acetyl peptide bonds were predicted in good agreement with observations in nonpolar solvents for the respective compounds. The conformational distributions with respect to proline Ψ are also in accord with experimental observations. For AcProMe2A, a model for a ‐Pro‐Pro‐sequence in a peptide chain, this study is the first to predict stable conformers for proline Ψ either ca. −50° or 140° for both cis and trans peptides.