Designed high affinity Cu2+ -Binding α-Helical foldamer

Nicoll, Andrew J., Miller, David James, Fütterer, Klaus, Ravelli, Raymond and Allemann, Rudolf Konrad ORCID: https://orcid.org/0000-0002-1323-8830 2006. Designed high affinity Cu2+ -Binding α-Helical foldamer. Journal of the American Chemical Society 128 (28) , pp. 9187-9193. 10.1021/ja061513u

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Abstract

The design, synthesis, and characterization of a folded high-affinity metal-binding peptide is described. Based on the previously described folded peptide NTH-18, in which an α-helix was constrained through two disulfide bonds to a C-terminal extension of noncanonical secondary structure, a peptide (1) was designed to contain two histidine residues in positions 3 and 7. Air oxidation of 1 led to the formation of peptide 2, which contained two intramolecular disulfide bonds. The presence of the two histidines significantly destabilized the α-helical structure of 2 when compared to NTH-18. However, CD spectroscopy revealed that the addition of certain transition metal ions allowed the reformation of a stable α-helix. CD, NMR, and EPR spectroscopy as well as MALDI-TOF mass spectrometry indicated that 2 bound to Cu2+ to form a 1:1 complex via the imidazoles of the two histidine side chains. A glycine displacement assay revealed a dissociation constant for this complex of 5 nM at pH 8, which is the lowest reported value for a designed Cu2+-binding peptide. This peptide displayed more than 100-fold selectivity for Cu2+ over Zn2+, Ni2+, and Co2+. The 1.05 Å crystal structure of the Cu(II)-complex of 2 revealed a square-pyramidal coordination geometry and confirmed that 2 bound to copper in an α-helical conformation via its two histidine side chains. The high affinity metal binding of peptide 2 demonstrates that metals can be used for the selective nucleation of α-helices.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Cardiff Catalysis Institute (CCI) Chemistry
Subjects:	Q Science > QD Chemistry
Publisher:	ACS Publications
ISSN:	0002-7863
Last Modified:	18 Oct 2022 13:08
URI:	https://orca.cardiff.ac.uk/id/eprint/12497

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