The design and study of metalloprotein models is the primary goal of the proposed research. Metal to ligand coordination will be employed as a means of defining the conformations of short peptides which are either covalently attached to a metalloporphyrin scaffold, or which form complexes with exogenous metalloporphyrins or transition metal ions. The functions of the metalloporphyrins and metal ions in the proposed systems mirror their roles in nature, for example as allosteric regulators of protein conformation and as templates for protein folding. Several of the proposed metalloprotein models have been designed to mimic the functions of known proteins.
Specific aims are to: 1) Prepare new helix-sandwiched porphyrins (HSP's) in order to more fully understand the factors which stabilize a-helices, particularly within the context of hemoproteins such as the globins. 2) Model the heme transport protein hemopexin by synthesizing dimeric peptides which fold into a-helical conformations upon binding iron porphyrins. 3) Employ metal ion binding to drive self-assembly of metalloprotein model compounds using peptides containing both bipyridyl amino acids and other, natural, metal-ligating amino acid side chains. 4) Prepare HSP's in which bipyridyl amino acids near the terminus of each peptide cooperate in the binding of metal ions. These bimetallo protein models will be used to model the activities of proteins such as the globins and cytochrome P450. 5) Study and catalogue information pertaining to the effect of structural changes in the HSP's on heme induced circular dichroism spectra in order to better understand these features in natural hemoproteins.
| Kennedy, M L; Silchenko, S; Houndonougbo, N et al. (2001) Model hemoprotein reduction potentials: the effects of histidine-to-iron coordination equilibrium. J Am Chem Soc 123:4635-6 |
| Silchenko, S; Sippel, M L; Kuchment, O et al. (2000) Hemin is kinetically trapped in cytochrome b(5) from rat outer mitochondrial membrane. Biochem Biophys Res Commun 273:467-72 |
| Lee, K H; Benson, D R; Kuczera, K (2000) Transitions from alpha to pi helix observed in molecular dynamics simulations of synthetic peptides. Biochemistry 39:13737-47 |
