HELIX INDUCTION AND SPRINGBOARD STRAIN IN PEPTIDE-SANDWICHED MESOHEMES

We report the results of studies of a series of water-soluble peptide adducts of iron mesoporphyrin IX (FeMPIX), In one group of compounds, the peptide-sandwiched mesohemes (PSMs; 1-5), two identical 13-residue peptides are connected to the propionate groups of FeMPIX via amide l inkages with N epsilon nitrogens of lysine (Lys) residues. The corresp onding monopeptide analogues of each PSM (1m-5m) have also been prepar ed. The imidazolyl side chain of a histidine (His) residue in each pep tide coordinates to the mesohemin iron. The compounds differ from one another in the relative positions of the His and Lys residues in the p eptide sequences. In 1, 2, 4, and 5 and the corresponding monopeptide systems, Fe-His coordination results in various extents of peptide hel ix induction in neutral aqueous solution. The peptides in 3 and 3m rem ain in random coil conformations. Helix content in 1-5 can be enhanced by addition of organic cosolvents, including 2,2,2-trifluoroethanol ( TFE) and 1-propanol (PrOH). Data from EPR spectroscopy and from pH tit rations suggest that in aqueous solution the folded forms of 3 and 5 ( in which both Fe-His bonds are intact) are less stable than the folded forms of the other PSMs. Addition of TFE or PrOH increases the stabil ity of the folded forms of 1, 2, and 4 by favoring helical conformatio ns for the peptides whether or not the Fe-His bonds are intact, thus e liminating the helix unwinding that occurs upon bond breakage in aqueo us solution. Increasing peptide helix content in 3 and 5 with TFE does little or nothing to increase the stability of their folded forms, co nsistent with the prediction that the His-Lys spacing in these compoun ds is not compatible with stable helical conformations for the peptide s, UV/vis spectra of the Fe(II) complexes of 3 and 5 are also consiste nt with reduced structural stability of these PSMs, as a sizable popul ation of pentacoordinate (high-spin) Fe(II) is in equilibrium with hex acoordinate (low-spin) Fe(II) at neutral pH, both in aqueous solution and in the presence of 30% (v/v) TFE at 8 degrees C. The Fe(II) comple xes of 1, 2, and 4 remain predominantly hexacoordinate in both solvent systems.