Metal Clips Induce Folding of a Short Unstructured Peptide into an α-Helix via Turn Conformations in Water. Kinetic versus Thermodynamic Products

Short peptides corresponding to two to four α-helical turns of proteins are not thermodynamically stable helices in water. Unstructured octapeptide Ac-His1*-Ala2-Ala3-His4*-His5*-Glu6-Leu7-His8*-NH2 (1) reacts with two [Pd(15NH2(CH2)2 15NH2)(NO3)2] in water to form a kinetically stable intermediate, [{Pden}2{(1,4)(5,8)-peptide}](2), in which two 19-membered metallocyclic rings stabilize two peptide turns. Slow subsequent folding to a thermodynamically more stable two-turn α-helix drives the equilibrium to [{Pden}2{(1,5)(4,8)-peptide}] (3), featuring two 22-membered rings. This transformation from unstructured peptide via turns to an α-helix suggests that metal clips might be useful probes for investigating peptide folding.