Conformational analysis of endomorphin-1 by molecular dynamics methods.

Endomorphin-1 (EM1, H-Tyr-Pro-Trp-Phe-NH2) is a highly potent and selective agonist for the mu-opioid receptor. A conformational analysis of this tetrapeptide was carried out by simulated annealing and molecular dynamics methods. EM1 was modeled in the neutral (NH2-) and cationic (NH-) forms of the N-terminal amino group. The results of NMR measurements were utilized to perform simulations with restrained cis and trans Tyr1-Pro2 peptide bonds. Preferred conformational regions in the Phi 2-Psi 2, Phi 3-Psi 3 and Phi 4-Psi 4 Ramachandran plots were identified. The g(+), g(-) and trans rotamer populations of the side-chains of the Tyr1, Trp3 and Phe4 residues were determined in chi 1 space. The distances between the N-terminal N atom and the other backbone N and O atoms, and the distances between the centers of the aromatic side-chain rings and the Pro2 ring were measured. The preferred secondary structures were determined as different types of beta-turns and gamma-turns. In the conformers of trans-EM1, an inverse gamma-turn can be formed in the N-terminal region, but in the conformers of cis-EM1 the N-terminal inverse gamma-turn is absent. Regular and inverse gamma-turns were observed in the C-terminal region in both isomers. These beta- and gamma-turns were stabilized by intramolecular H-bonds and bifurcated H-bonds.