title: Alpha-turn mimetics: short peptide alpha-helices composed of cyclic metallopentapeptide modules.
abstract: Alpha-Helices are key structural components of proteins and important recognition motifs in biology. Short peptides (<or=15 residues) corresponding to these helical sequences are rarely helical away from their stabilizing protein environments. New techniques for stabilizing short peptide helices could be valuable for studying protein folding, modeling proteins, creating artificial proteins, and may aid the design of inhibitors or mimics of protein function. This study reports the facile incorporation of 3- and 4-alpha turns in 10-15 residue peptides through formation in situ of multiple cyclic metallopeptide modules [Pd(en)(H*XXXH*)](2+). The nonhelical peptides Ac-H*ELTH*H*VTDH*-NH(2) (1), Ac-H*ELTH*AVTDYH*ELTH*-NH(2) (2), and Ac-H*AAAH*HELTH*H*VTDH*-NH(2) (3) (H is histidine-methylated at imidazole-N3) react in N,N-dimethylformamide (DMF) or water with 2, 2, and 3 molar equivalents, respectively, of [Pd(en)(NO(3))(2)] to form exclusively [Pd(2)(en)(2)(Ac-H*ELTH*H*VTDH*-NH(2))](4+) (4), [Pd(2)(en)(2)(Ac-H*ELTH*AVTDYH*ELTH*-NH(2))](4+) (5), and [Pd(3)(en)(3)(Ac-H*AAAH*HELTH*H*VTDH*-NH(2))](6+) (6), characterized by mass spectrometry, 1D and 2D (1)H- and 1D (15)N-NMR spectroscopy. Despite the presence of multiple histidines and other possible metal-binding residues in these peptides, 2D (1)H NMR spectra reveal that Pd(en)(2+) is remarkably specific in coordinating to imidazole-N1 of only (i, i + 4) pairs of histidines (i.e., only those separated by three amino acids), resulting in 4-6 made up of cyclic metallopentapeptide modules ([Pd(en)(H*XXXH*)](2+))(n), n = 2, 2, 3, respectively, each cycle being a 22-membered ring. We have previously shown that a single metallopentapeptide can nucleate alpha-helicity (Kelso et al., Angew. Chem., Int. Ed. 2003, 42, 421-424.). We now demonstrate its use as an alpha-turn-mimicking module for the facile conversion of unstructured short peptides into helices of macrocycles and provide 1D and 2D NMR spectroscopic data, structure calculations via XPLOR and NMR analysis of molecular flexibility in solution (NAMFIS), and CD spectra in support of the alpha-helical nature of these monomeric metallopeptides in solution.
authors.affiliation: Centre for Drug Design and Development, Institute for Molecular Bioscience, University of Queensland, Brisbane, Qld 4072, Australia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kelso
authors.forename: Renée L
authors.initials: RL
authors.lastname: Beyer
authors.forename: Huy N
authors.initials: HN
authors.lastname: Hoang
authors.forename: Ami S
authors.initials: AS
authors.lastname: Lakdawala
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
authors.forename: Warren V
authors.initials: WV
authors.lastname: Oliver
authors.forename: Tom A
authors.initials: TA
authors.lastname: Robertson
authors.forename: Trevor G
authors.initials: TG
authors.lastname: Appleton
authors.forename: David P
authors.initials: DP
authors.lastname: Fairlie
mesh_terms: D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry; D002942:Circular Dichroism; D013058:Mass Spectrometry; D008667:Metalloproteins / Q000138:chemical synthesis / Q000737:chemistry*; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry*; D017433:Protein Structure, Secondary; D013816:Thermodynamics
chemical_list: D008667:Metalloproteins; D010456:Peptides, Cyclic