title: Reversible Folding of a β-Hairpin Peptide by a Metal-Chelating Amino Acid.
abstract: 5-(1-Hydroxy-pyridin-2(1H)-onyl)-l-alanine (Hop) is a N-hydroxy-1,2-pyridone functionalized α-amino acid with the desired metal-chelating properties of DOPA (3,4-dihydroxy phenylalanine) but without its unwanted redox activity. The Fmoc-protected amino acid Fmoc-l-Hop(tBu)-OH (11) was synthesized from glycine phosphonate followed by enzymatic hydrolysis of the methyl ester yielding the Hop l-isomer in 96 % ee. The amino acid 11 is used in automated peptide synthesis for the assembly of a 14mer β-hairpin peptide with the sequence [dsb1, 14]H-CHXETGKHGHKLVC-OH (X=W, l-Hop). While the 10 π electron containing indole side chain of l-Trp in peptide 14 completes the formation of a hydrophobic cluster and results in 90 % folding, the folded fraction is significantly decreased to approximately 30 % for the 6 π electron l-Hop side chain in peptide 16. Metal chelation of Ga3+reconstitutes the folding of 16 to above 60 % due to the formation of the Ga(16)3trimer. The chelation process of 16 is monitored by NMR spectroscopy and the subsequent release of Ga3+by a competitive metal chelator exemplifies the reversible oligomerization of peptide epitopes by metal chelation, bearing the opportunity to synthesize protein-sized aggregates on the basis of reversible chemistry in water.
authors.affiliation: Department of Chemistry, Philipps-University Marburg, Hans-Meerwein-Str. 4, 35032, Marburg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Reutzel
authors.affiliation: Department of Chemistry, Philipps-University Marburg, Hans-Meerwein-Str. 4, 35032, Marburg, Germany.
authors.forename: Timm M
authors.initials: TM
authors.lastname: Diogo
authors.affiliation: Department of Chemistry, Philipps-University Marburg, Hans-Meerwein-Str. 4, 35032, Marburg, Germany.
authors.forename: Armin
authors.identifier: http://orcid.org/0000-0001-8096-2266
authors.initials: A
authors.lastname: Geyer
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry*; D056831:Coordination Complexes / Q000737:chemistry*; D006868:Hydrolysis; D057927:Hydrophobic and Hydrophilic Interactions; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008670:Metals / Q000737:chemistry; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D017510:Protein Folding; D055503:Protein Multimerization; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D056831:Coordination Complexes; D008670:Metals; D010455:Peptides
keywords: NMR spectroscopy; hydroxypyridones; metal chelation; oligomerization; peptides