Journal of Molecular Structure (Theochem), 164 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPO (1988) 153-164 Elsevier Science Publishers B.V., Amsterdam - Printed in The Netherlands CONFORMATIONAL PROPERTIES OF THE ANALGESIC PEPTIDE zyxwvutsrqponm DERMORPHIN AND THEIR RELATIONSHIPS TO BIOLOGICAL ACTIVITY* GRAZIELLA RANGHINO, CAMILLO TOSI, LUISA BARINO, RAIMONDO SCORDAMAGLIA and ROBERTO FUSCO Istituto Guido Donegani, Via G. Fauser 4, 28100 Novara (Italy) (Received 4 June 1987) ABSTRACT The conformational properties of the analgesic heptapetide dermorphin were investi- gated using potential energy calculations, by applying a variety of computer programs, especially aimed at detecting the low-energy minima of intramolecular potential energy functions. The most stable conformations are bent, due to various types of intramolecular hydrogen bonds, while the energy of extended structures is somewhat higher. This is in keeping with the conclusions drawn from experimental measurements in solution, that the pharmacological activity of dermorphin is likely to be due to a peculiar folded conforma- tion, mainly resulting from the presence of Ala-2 in configuration D at the N-end and the Pro-6 - Ser.7 sequence, endowed with a high p-turn potential, at the C-end. A comparison was also made between the low-energy regions, as predicted by different force fields, and these predictions were found to be in substantial agreement. INTRODUCTION Dermorphin (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NHz) is a natural heptapeptide isolated from the skin of frogs of the genus zyxwvutsrqponmlkjihgfedcb Phy llomedusa and characterized by a long lasting opiate-like activity [l, 21. It is a potent ,u-receptor agonist, with some affinity for a-receptor sites [3]. The presence of a D-amino acid residue, quite unusual in materials of non-microbial origin, plays a crucial role for analgesic activity; the synthetic analogue with L-Ala in position 2 is completely inactive in biological tests [4] . This feature is of particular interest, if one considers that D residues have been introduced in position 2 of some synthetic enkephalins to improve their biological activity [5]. It should also be noted that the sequence of dermorphin bears some resemblance to the sequence of enkephalins (Tyr-Gly-Gly-Phe-Leu or Met), with two remarkable differences; the presence of a second Tyr residue *Presented, in part, at the Workshop on Biochemistry and Pharmacology of Neuropeptides and Their Enzymatic Degradation, Florence, 25 June 1986 (by R. F.), and at the XXXVth Colloquium on the Protides of Biological Fluids, Brussels 27-29 April 1987 (by G. R.). 0166-1280/88/$03.50 0 1988 Elsevier Science Publishers B.V.