Metallothioneins (MTs) are a ubiquitous class of small metal-binding proteins involved in metal homeostasis and detoxification. While known for their high affinity for d 10 metal ions, there is a surprising dearth of thermodynamic data on metals binding to MTs. In this study, Zn 2+ and Cu + binding to mammalian metallothionein-3 (MT-3) were quantified at pH 7.4 by isothermal titration calorimetry (ITC). Zn 2+ binding was measured by chelation titrations of Zn 7 MT-3, while Cu + binding was measured by Zn 2+ displacement from Zn 7 MT-3 with competition from glutathione (GSH). Titrations in multiple buffers enabled a detailed analysis that yielded condition-independent values for the association constant ( K ) and the change in enthalpy (Δ H ) and entropy (Δ S ) for these metal ions binding to MT-3. Zn 2+ was also chelated from the individual α and β domains of MT-3 to quantify the thermodynamics of inter-domain interactions in metal binding. Comparative titrations of Zn 7 MT-2 with Cu + revealed that both MT isoforms have similar Cu + affinities and binding thermodynamics, indicating that Δ H and Δ S are determined primarily by the conserved Cys residues. Inductively coupled plasma mass spectrometry (ICP-MS) analysis and low temperature luminescence measurements of Cu-replete samples showed that both proteins form two Cu 4 + –thiolate clusters when Cu + displaces Zn 2+ under physiological conditions. Comparison of the Zn 2+ and Cu + binding thermodynamics reveal that enthalpically-favoured Cu + , which forms Cu 4 + –thiolate clusters, displaces the entropically-favoured Zn 2+ . These results provide a detailed thermodynamic analysis of d 10 metal binding to these thiolate-rich proteins and quantitative support for, as well as molecular insight into, the role that MT-3 plays in the neuronal chemistry of copper.
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Thermodynamic and kinetic studies of H 2 and N 2 binding to bimetallic nickel-group 13 complexes and neutron structure of a Ni(η 2 -H 2 ) adduct
Understanding H 2 binding and activation is important in the context of designing transition metal catalysts for many processes, including hydrogenation and the interconversion of H 2 with protons and electrons. This work reports the first thermodynamic and kinetic H 2 binding studies for an isostructural series of first-row metal complexes: NiML, where M = Al ( 1 ), Ga ( 2 ), and In ( 3 ), and L = [N( o -(NCH 2 P i Pr 2 )C 6 H 4 ) 3 ] 3− . Thermodynamic free energies (Δ G °) and free energies of activation (Δ G ‡ ) for binding equilibria were obtained via variable-temperature 31 P NMR studies and lineshape analysis. The supporting metal exerts a large influence on the thermodynamic favorability of both H 2 and N 2 binding to Ni, with Δ G ° values for H 2 binding found to span nearly the entire range of previous reports. The non-classical H 2 adduct, (η 2 -H 2 )NiInL ( 3 -H 2 ), was structurally characterized by single-crystal neutron diffraction—the first such study for a Ni(η 2 -H 2 ) complex or any d 10 M(η 2 -H 2 ) complex. UV-Vis studies and TD-DFT calculations identified specific electronic structure perturbations of the supporting metal which poise NiML complexes for small-molecule binding. ETS-NOCV calculations indicate that H 2 binding primarily occurs via H–H σ-donation to the Ni 4p z -based LUMO, which is proposed to become energetically accessible as the Ni(0)→M( iii ) dative interaction increases for the larger M( iii ) ions. Linear free-energy relationships are discussed, with the activation barrier for H 2 binding (Δ G ‡ ) found to decrease proportionally for more thermodynamically favorable equilibria. The Δ G ° values for H 2 and N 2 binding to NiML complexes were also found to be more exergonic for the larger M( iii ) ions.
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- Award ID(s):
- 1665010
- NSF-PAR ID:
- 10148075
- Date Published:
- Journal Name:
- Chemical Science
- Volume:
- 10
- Issue:
- 29
- ISSN:
- 2041-6520
- Page Range / eLocation ID:
- 7029 to 7042
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/C9SC02018G
