Design of a Peptidic Turn with High Affinity for Hg^II

A four amino acid peptide containing the β-turn template <i>d</i>Pro-Pro in the middle and two cysteines (Cys) in the terminal positions (CdPPC) has been synthesized and its mercury­(II) coordination properties studied using different spectroscopic methods. The UV–vis, CD, ^199mHg PAC, and Raman spectroscopic studies indicate the binding of Hg^II to the two Cys, forming the dithiolatemercury­(II) complex Hg­(CdPPC). Electrospray ionization mass spectrometry corroborates the 1:1 complex formation. A log <i>K</i> = 40.0 was determined for the formation constant of the Hg­(CdPPC) complex using competition potentiometric studies. Replacement of the <i>d</i>Pro-Pro motif by a Pro-Pro unit generated a peptide (CPPC) capable of forming a similar species [Hg­(CPPC)] but showing a lower affinity for Hg^II (at least 3–3.5 orders of magnitude lower). The introduction of the <i>d</i>Pro-Pro motif is crucial to induce the folding of the CdPPC peptide into a β-turn, preorganizing the two Cys for mercury­(II) coordination. While the simple <i>d</i>Pro-Pro unit mimics the overall preorganization achieved by the protein scaffold in metalloproteins containing the conserved metal ion chelation unit CXXC, the high thiophilicity of this metal stabilizes the final complex in a wide pH range (1.1–10). Using computational modeling, the structures of two conformers for Hg­(CdPPC) have been optimized that differ mainly in the orientation of the plane containing S–Hg–S with respect to the anchoring C atoms

Application of ^204mPb Perturbed Angular Correlation of γ-rays Spectroscopy in Coordination Chemistry

^204mPb perturbed angular correlation of γ-rays (PAC) spectroscopy has been applied successfully for the first time to detect the nuclear quadrupole interaction in a lead­(II) coordination compound in a molecular crystal [tetraphenylarsonium lead­(II) isomaleonitriledithiolate ([AsPh₄]₄[Pb₂(i-mnt)₄])]. The recorded parameters from a powder crystalline sample are ν_Q = 0.178(1) GHz and η = 0.970(7). The electric field gradient (EFG) was determined at the PW91/QZ4P level including relativistic effects using the two-component zeroth-order regular approximation method for both the [Pb­(i-mnt)₂]^2– monomer and the [Pb₂(i-mnt)₄]^4– dimer. Only the EFG for the latter compares favorably with the experimental data, indicating that the picture of this complex as a prototypical hemidirected coordination geometry with a stereochemically active lone pair on lead­(II) is inadequate. Advantages and limitations of ^204mPb PAC spectroscopy as a novel technique to elucidate the electronic and molecular structures of lead-containing complexes and biomolecules are presented

Rapid Exchange of Metal between Zn₇–Metallothionein-3 and Amyloid-β Peptide Promotes Amyloid-Related Structural Changes

Metal ions, especially Zn²⁺ and Cu²⁺, are implemented in the neuropathogenesis of Alzheimer’s disease (AD) by modulating the aggregation of amyloid-β peptides (Aβ). Also, Cu²⁺ may promote AD neurotoxicity through production of reactive oxygen species (ROS). Impaired metal ion homeostasis is most likely the underlying cause of aberrant metal–Aβ interaction. Thus, focusing on the body’s natural protective mechanisms is an attractive therapeutic strategy for AD. The metalloprotein metallothionein-3 (MT-3) prevents Cu–Aβ-mediated cytotoxicity by a Zn–Cu exchange that terminates ROS production. Key questions about the metal exchange mechanisms remain unanswered, e.g., whether an Aβ–metal–MT-3 complex is formed. We studied the exchange of metal between Aβ and Zn₇–MT-3 by a combination of spectroscopy (absorption, fluorescence, thioflavin T assay, and nuclear magnetic resonance) and transmission electron microscopy. We found that the metal exchange occurs via free Cu²⁺ and that an Aβ–metal–MT-3 complex is not formed. This means that the metal exchange does not require specific recognition between Aβ and Zn₇–MT-3. Also, we found that the metal exchange caused amyloid-related structural and morphological changes in the resulting Zn–Aβ aggregates. A detailed model of the metal exchange mechanism is presented. This model could potentially be important in developing therapeutics with metal-protein attenuating properties in AD

Controlling Self-Assembly of a Peptide-Based Material via Metal-Ion Induced Registry Shift

Peptide <b>TZ1C2</b> can populate two distinct orientations: a staggered (out-of-register) fibril and an aligned (in-register) coiled-coil trimer. The coordination of two cadmium ions induces a registry shift that results in a reversible transition between these structural forms. This process recapitulates the self-assembly mechanism of native protein fibrils in which a ligand binding event gates a reversible conformational transition between alternate forms of a folded peptide structure