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.