abstract
- In a previous paper (Zhorov and Ananthanarayanan, J. Biomol, Struct. Dynam. 1995, 13:1-13) we had calculated the minimum-energy conformations of monoprotonated and zwitterionic mu-opioid peptides and demonstrated the remarkable similarity between Ca(2+)-bound morphine on the one hand and the Ca(2+)-bound forms of these peptides on the other. We postulated that the Ca(2+)-bound forms of mu-opioids would activate the mu-receptor. To assess further the involvement of multiple positive charges on some of the mu-opioid ligands in their interaction with the receptor, we have, in this work, studied the geometry of five mu-opioid peptides containing two to four protonated groups and having chemical structures essentially different from the endogenous mu-opioid peptide Met-enkephalin (EK). Conformational space was searched using the Monte Carlo-with-energy-minimization method. Ca(2+)-bound forms of the selected peptides were found to be energetically unfavourable implying that one of the protonated groups plays a role similar to that Ca2+ plays in EK-Ca2+ complex. Bioactive conformations of the polyprotonated peptides were then selected using the criteria formulated earlier for Ca(2+)-bound ligands as well as additional criteria requiring ligands to have an elongated conical overall shape complementary to the interface between the transmembrane segments of mu-receptor. Low-energy conformations meeting these criteria were found in all the peptides considered, the protonated groups being separated from each other by about 8 and 16 A. The possible role of the ligands' cationic groups in mu-receptor activation is discussed.