Abstract
Tetrapeptides containing a Cys-Gly-Cys motif and a propensity to adopt a reverse-turn structure were synthesized to evaluate how O-, N-, H-, and aromatic π donor groups might contribute to mercury(II) complex formation. Tetrapeptides Xaa-Cys-Gly-Cys, where Xaa is glycine, glutamate, histidine, or tryptophan, were prepared and reacted with mercury(II) chloride. Their complexation with mercury(II) was studied by spectroscopic methods and computational modeling. UV-vis studies confirmed that mercury(II) binds to the cysteinyl thiolates as indicated by characteristic ligand-to-metal-charge-transfer transitions for bisthiolated S-Hg-S complexes, which correspond to 1 : 1 mercury-peptide complex formation. ESI-MS data also showed dominant 1 : 1 mercury-peptide adducts that are consistent with double deprotonations from the cysteinyl thiols to form thiolates. These complexes exhibited a strong positive circular dichroism band at 210 nm and a negative band at 193 nm, indicating that these peptides adopted a β-turn structure after binding mercury(II). Theoretical studies confirmed that optimized 1 : 1 mercury-peptide complexes adopt β-turns stabilized by intramolecular hydrogen bonds. These optimized structures also illustrate how specific N-terminal side-chain donor groups can assume intramolecular interactions and contribute to complex stability. Fluorescence quenching results provided supporting data that the indole donor group could interact with the coordinated mercury. The results from this study indicate that N-terminal side-chain residues containing carboxylate, imidazole, or indole groups can participate in stabilizing dithiolated mercury(II) complexes. These structural insights on peripheral mercury-peptide interactions provide additional understanding of the chemistry of mercury(II) with side-chain donor groups in peptides.
Highlights
Bis-cysteinyl sequences are present in many metalloproteins that play an important role in metal detoxification, regulation, homeostasis, or transport. e signature Cys-Xaa-Cys and Cys-Xaa-Xaa-Cys sequences are found in various types of metal-binding proteins such as metallothioneins [1, 2], MerP [3] and MerA [4], HAH1 [5], and Atox [6]
Design and Synthesis of Bis-Cysteinyl Tetrapeptides. e bis-cysteinyl tetrapeptides (Figure 1) were prepared by microwave-irradiated solid phase peptide synthesis following the standard Fmoc-strategy as previously described for analogous compounds [22, 24]. eir sequence was designed to have a propensity to adopt the common β-turn involving four amino acids [12]
UV-Vis Spectrophotometry. e formation of complexes between mercury(II) and each tetrapeptide was studied by monitoring the ligand-to-metal charge-transfer (LMCT) transitions for S---Hg bonds in the mid-UV energy range
Summary
Bis-cysteinyl sequences are present in many metalloproteins that play an important role in metal detoxification, regulation, homeostasis, or transport. e signature Cys-Xaa-Cys and Cys-Xaa-Xaa-Cys sequences are found in various types of metal-binding proteins such as metallothioneins [1, 2], MerP [3] and MerA [4], HAH1 [5], and Atox [6]. An oligopeptide containing the Cys-Ala-AlaCys sequence, found in the MerP protein, retained its heavy metal-binding activity [7] Constrained tetrapeptides, such as Cys-dPro-Pro-Cys, have been designed to preorganize the two cysteine residues so that their thiol donor groups are positioned as “anchors” for mercury(II) coordination [8]. The arrangement or preorganization of metal coordinating groups/atoms is fundamentally important at the primary metal coordination site of metalloproteins, their stability or function is often linked to their local environment. Such features have been demonstrated in the design principles of model systems for the binding and Bioinorganic Chemistry and Applications activation of dioxygen by transition-metal complexes. Borovik and coworkers designed various tripodal ligands containing local intramolecular H-bonding networks around transition metal ions [9,10,11]
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