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Updated: Jan 17, 2026
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Structure and Coordination Determination of Peptide-metal Complexes Using 1D and 2D 1H NMR
Published on: December 16, 2013
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Histidine Nτ-Imidazole Ligation to Copper in Proteins: Innate or Entatic?
Tao A G Large1, Richard Hage1, Jasper Ainsworth1,2
1Department of Chemistry, Stanford University, Stanford, California 94305, United States.
Journal of the American Chemical Society
|September 23, 2025
Summary
Histidine's nitrogen atoms show a natural preference for binding copper(II) at the Nτ site, crucial for enzyme function. The Nπ site binding in electron transfer sites likely requires protein influence.
Area of Science:
- Biochemistry
- Bioinorganic Chemistry
- Enzymology
Background:
- Histidine's imidazole ring offers versatile metal binding via Nπ and Nτ atoms.
- Copper enzymes utilize these nitrogen atoms differently: Nτ for substrate activation, Nπ for electron transfer.
Purpose of the Study:
- To determine the innate thermodynamic preference of histidine nitrogen atoms for copper(II) binding.
- To investigate the structural basis for functional differentiation in copper enzyme active sites.
Main Methods:
- Ligand competition experiments at -145 °C using synthetic μ-η²:η²-peroxodicopper(II) cores.
- Spectroscopic analysis of related complexes with methylated imidazoles.
Main Results:
- Histidine exhibits an intrinsic thermodynamic preference for Nτ-ligation to Cu(II) centers.
- This preference is attributed to enthalpic (basicity) and entropic (molecular volume) factors.
- Nπ-ligation appears to be protein-stabilized (entatic), not thermodynamically innate.
Conclusions:
- The Nτ-ligation in copper enzymes is the inherent thermodynamic preference of histidine.
- The Nπ-ligation observed in electron transfer sites suggests protein-mediated structural influence.
- This distinction serves as a functional indicator for biological copper sites.
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