α-Turn Mimetics:  Short Peptide α-Helices Composed of Cyclic Metallopentapeptide Modules

• Published in: Journal of the American Chemical Society Vol. 126; no. 15; pp. 4828 - 4842
• Main Authors: Kelso, Michael J, Beyer, Renée L, Hoang, Huy N, Lakdawala, Ami S, Snyder, James P, Oliver, Warren V, Robertson, Tom A, Appleton, Trevor G, Fairlie, David P
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 21.04.2004; Amer Chemical Soc
• Subjects: Biological and medical sciences; Biomimetic Materials - chemical synthesis; Biomimetic Materials - chemistry; Chemistry; Chemistry, Multidisciplinary; Circular Dichroism; Fundamental and applied biological sciences. Psychology; Mass Spectrometry; Metalloproteins - chemical synthesis; Metalloproteins - chemistry; Models, Molecular; Molecular biophysics; Nuclear Magnetic Resonance, Biomolecular; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - chemistry; Physical Sciences; Protein Structure, Secondary; Science & Technology; Structure in molecular biology; Supramolecular structure; Thermodynamics; COPPER(II) COMPLEXES; PROTEIN CONFORMATIONS; CIRCULAR-DICHROISM; AMINO-ACIDS; SECONDARY STRUCTURE; STABILITY-CONSTANTS; ION ENHANCED HELICITY; PROTON DISTANCE CONSTRAINTS; INTERPROTON DISTANCE; COUPLING-CONSTANTS; Cationic complex; Palladium Complexes; Organic ligand; Homonuclear correlation; NMR spectrometry; Transition metal Complexes; Conformational changes; Aminoacid polymer; Two dimension spectrometry; Solution structure; Supramolecular structure; Platinoid Complexes; Helical structure; Aqueous solution
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja037980i

α-Helices are key structural components of proteins and important recognition motifs in biology. Short peptides (≤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-α 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*-NH2 (1), Ac-H*ELTH*AVTDYH*ELTH*-NH2 (2), and Ac-H*AAAH*H*ELTH*H*VTDH*-NH2 (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)(NO3)2] to form exclusively [Pd2(en)2(Ac-H*ELTH*H*VTDH*-NH2)]4+ (4), [Pd2(en)2(Ac-H*ELTH*AVTDYH*ELTH*-NH2)]4+ (5), and [Pd3(en)3(Ac-H*AAAH*H*ELTH*H*VTDH*-NH2)]6+ (6), characterized by mass spectrometry, 1D and 2D 1H- and 1D 15N-NMR spectroscopy. Despite the presence of multiple histidines and other possible metal-binding residues in these peptides, 2D 1H 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 α-helicity (Kelso et al., Angew. Chem., Int. Ed. 2003, 42, 421−424.). We now demonstrate its use as an α-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 α-helical nature of these monomeric metallopeptides in solution.