Pro-D-NMe-Amino Acid and D-Pro-NMe-Amino Acid: Simple, Efficient Reverse-Turn Constraints

The design of mimetics that, when incorporated into a peptide, constrain it to adopt a reverse turn is currently of considerable interest. Numerous bicyclic dipeptide surrogates have been suggested which fix two of the four backbone dihedral angles of residues i + 1 and i + 2 of the turn. In this paper, we report the conformational analysis of tetrapeptides containing several bicyclic mimetics, sequences containing proline and other N-methylamino acids in the i + 1 and i + 2 positions of the turn, and control peptide sequences using a Monte Carlo conformational search followed by molecular dynamics simulation in water as implicitly represented by a solvation model. These studies indicate that the sequences D-Pro-N-methylamino acid (D-Pro-NMe-AA) and Pro-D-NMe-AA are effective at stabilizing the trans conformer of the amide bond between residues i + 1 and i + 2 and constraining three of the four backbone dihedral angles to those associated with structures which satisfy several criteria for reverse turns. In many cases, these sequences were more effective than more complicated polycyclic mimetics. D-Pro-NMe-AA and Pro- D-NMe-AA are compatible with conventional peptide synthesis methods and should provide a simple method to probe receptors for reverse-turn recognition through combinatorial libraries and structure-activity studies.