Conformational Heterogeneity about Pipecolic Acid Peptide Bonds: Conformational, Thermodynamics, and Kinetic Aspects

Cis-trans isomerization about pipecolic peptide bonds has been studied using a set of designed tetrapeptides of the sequence acetyl-Gly-X-Pip-Gly-carboxamide (GXPipG), where X = A, F, Y, W, or cyclohexylalanine (Cha). The substitution of a pipecolic residue for a proline leads to (1) a significant increase of the population of the cis conformer, (2) a reduction in the Van't Hoff enthalpy for isomerism, and (3) acceleration of the rates of isomerization. GAPipG and GChaPipG are unstructured, and isomerization is controlled by local steric effects between the α and ε positions of the pipecolic ring and the α position of the preceding residue. The fraction of the cis isomer is the same for these two peptides, indicating that the bulk of the preceding amino acid does not play a significant role in influencing the equilibrium. In the trans form of the aromatic containing peptides, an i to i + 2 aromatic-amide interaction is observed, and in the cis form a stabilizing interaction between the aromatic residue and the succeeding pipecolic ring is observed. The sign of the Van't Hoff enthalpy indicates that the cis conformer is enthalpically favored for the aromatic containing peptides. The rate of isomerization for the aromatic containing peptides are reduced relative to GAPipG.