CONFORMATIONAL ENERGY STUDIES OF LINEAR DIPEPTIDES H-X-L-PRO-OH

Empirical conformational energy calculations with the use of ECEPP energy functions have been carried out for linear dipeptides H‐X‐L‐Pro‐OH, with X = Gly, L‐Ala, D‐Ala, L‐Leu, D‐Leu, L‐Phe, and D‐Phe, in different states of protonation of the end groups. The results of these calculations are compared with the previously reported experimental equilibrium populations for the cis and trans isomers of the X‐Pro bond in the different species. For all the protonation states of the seven dipeptides, the calculated nonbonded interactions and the conformational entropy term lead to a preference of the trans forms over the cis isomers by at least 1 kcal/mol. The electrostatic interactions stabilize the cis conformations in all species except the cationic forms of the D,L‐peptides, and it could further be shown that only the carbonyl group of X and the two end groups contribute significantly to the total electrostatic energy. One of the principal results of the experimental studies, i.e., the occurrence of 5–15% cis‐proline in all the peptides with an uncharged C‐terminus, was corroborated by our investigation of the cationic species. A detailed assessment of the electrostatic contribution to the total energy of the different conformations of H‐Gly‐L‐Pro‐OH indicates that the standard ECEPP parameters tend to overestimate the electrostatic interactions in aqueous solutions of the X‐Pro dipeptides. Copyright © 1979 John Wiley & Sons, Inc.