Conformational flexibility in enkephalins: Solvent dependent transitions in peptides with Gly-Gly segments detected by circular dichroism

Abstract

The widespread interest in developing structure-activity correlations for opioid peptides [1-3] has led to a large number of investigations on the preferred solution conformations of enkephalins [4-11]. The results of these studies have led to proposals ranging from \beta-turn conformations. With ${Gly}^2-{Gly}^3$ [14] or ${Gly}^3-{Phe}^4$ [4-10] as the corner residues. Evidence for the lack of preferred conformations in solutions, resulting from dynamic averaging between an ensemble of structures, has also been presented [11]. While a consensus has yet to be reached on the solution conformations of enkephalins, there is general agreement that receptor interactions presumably involve a folded, defined conformation of the penta-peptide [12-14]. The recognition of multiple receptor sites for opioid ligands [15-17], has provided a further impetus for studies of conformational flexibility in enkephalins, with the possibility that interaction at \mu and \delta sites may be mediated through different conformations of the peptides [18]. Here, we describe an unusual solvent-dependent conformational transition, in the protected fragment $Boc-Gly-Gly-Phe-Met.{NH}_2$ and ${Met}_5$-enkephalinamide which is abolished on restricting conformational freedom by substitution of Gly by \alpha-aminoisobutyryl (Aib) residues [19,20].