Structural Consequences of Metal Complexation of cyclo(Pro-Phe-Phe-Ala-Xaa)2 Decapeptides

The conformational features of both free and Ca2+-complexed cyclo-[Pro-Phe-Phe-Ala-Xaa]2 (with Xaa=Glu(OtBu), Lys(ClZ), Leu, and Ala) in soln. have been detd. by NMR spectroscopy and extensive distance-geometry calcns. The decapeptides are conformationally homogeneous in soln. and show common structural features in their free and complexed forms. The structures of the free form contain only trans peptide bonds and are topol. similar to the structure of gramicidin-S, folded up in two antiparallel extended structures, stabilized by interstrand hydrogen bonds, and closed at both ends by two b-turns. In contrast, the Ca2+-complexed peptides present two cis peptide bonds and are generally similar to those obsd. for the metal-complexed forms of antamanide and related analogs, folded into a saddle shape with two b-turns. The Glu(OtBu)-, Leu-, and Lys(ClZ)-contg. peptides examd. here maintain the biol. activity of the cyclolinopeptide A in their ability to competitively inhibit cholate uptake. The natural antamanide and cyclolinopeptide A are both able to inhibit the uptake of bile salts into hepatocytes. They share the same postulated active sequence Pro-Phe-Phe. Based on our structural results, we conclude that the ability to adopt a global conformation, characterized by a clear amphipathic sepn. of hydrophobic and hydrophilic surfaces, is an important feature for the functioning of this class of peptides.