CONFORMATIONAL-ANALYSIS OF REVERSE-TURN CONSTRAINTS BY N-METHYLATION AND N-HYDROXYLATION OF AMIDE BONDS IN PEPTIDES AND NONPEPTIDE MIMETICS

Several non-peptide systems have been designed to mimic different type s of reverse turns. The incorporation of some of these mimetics into b iologically active peptides has led to peptidomimetics with enhanced a ctivity or metabolic stability. This paper reports the conformational analysis of tetrapeptides containing several bicyclic mimetics, sequen ces containing proline, other N-methyl and N-hydroxy amino acids, and pipecolic acid at residue i + 2 of the turn, and control peptide seque nces using the Monte Carlo/stochastic dynamics simulation with the new set of AMBER parameters for proline-containing peptides in water as implicitly represented by the GB/SA solvation model. Simple N-methylat ion (Pro-D-NMeAA and D-Pro-NMeAA) and N-hydroxylation of the amide bon d between residues i + 1 and i + 2 or inclusion of the larger ring hom olog pipecolic acid (D-Pro-Pip) in the third position (i + 2) causes s ignificant nucleation of reverse-turn structures. Spirotricycle analog s restrict three of the four torsion angles that characterize the type II beta-turn. Spirolactam analogs also restrict two of the four torsi on angles as effective beta-turn constraints. However, the geometry of a turn induced by indolizidinone and BTD differs significantly from t hat of an ideal beta-turn and (S)-indolizidinone is more effective as a reverse turn than as a beta-turn mimetic. These systems provide usef ul conformational constraints when incorporated into the structure of selected bioactive peptides. Such analogs can scan receptors for biolo gical recognition of beta-turn scaffolds with oriented side chains thr ough combinatorial libraries to efficiently develop three-dimensional structure-activity relationships.