Conformational and Electrostatic Similarity Between Polyprotonated and Ca²⁺-Boundμ-Opioid Peptides

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 zwitterionicμ-opioid peptides and demonstrated the remarkable similarity between Ca²⁺-bound morphine on the one hand and the Ca²⁺-bound forms of these peptides on the other. We postulated that the Ca²⁺-bound forms ofμ-opioids would activate theμ-receptor. To assess further the involvement of multiple positive charges on some of theμ-opioid ligands in their interaction with the receptor, we have, in this work, studied the geometry of fiveμ-opioid peptides containing two to four protonated groups and having chemical structures essentially different from the endogenousμ-opioid peptide Met-enkephalin (EK). Conformational space was searched using the Monte Carlo-with-energy-minimization method. Ca²⁺-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 Ca²⁺-bound ligands as well as additional criteria requiring ligands to have an elongated conical overall shape complementary to the interface between the transmembrane segments ofμ-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 Å. The possible role of the ligands' cationic groups inμ-receptor activation is discussed.