In chemistry, nature-inspired solutions are often the most trivial and effective ones. Histidine rich sequences are used commercially in immobilized metal affinity chromatography (IMAC) as molecular ‘anchors’ that bind to a metal ion (usually nickel), immobilized by chelation with nitrilotriacetic acid (NTA) bound to a solid support. The typical (His)₆ tag, present at the C- or N-terminus of a protein which is meant to be purified, has been successfully used for decades. Consecutive histidines are the common denominator for both His-tags used in molecular biology and for quite remote biological phenomena – polyhistidine sequences are found in some bacterial chaperones, in Zn²⁺ transporters, prion proteins, in histidine-rich glycoproteins (HRG), which posses a massive amount of functions, in some snake venoms and antimicrobial peptides. This work debates on two questions – first, why were such sequences chosen by nature to exist in some parts of specific, sometimes evolutionally remote proteins, and second, are we right about choosing the polyhistidine motif as the strongest metal binder?

The Hpn and HspA proteins from H. pylori are significant for nickel homeostasis and protect the cells from higher concentrations of external metal ions. Both proteins have a unique histidine- and cysteine-rich domain at the C terminus. The interactions of Ni²⁺, Bi³⁺, Zn²⁺ and Cd²⁺ ions with C-terminal Ac–CCSTSDSHHQ–NH₂ and Ac–EEGCCHGHHE–NH₂ fragments from Hpn and the Ac–GSCCHTGNHD–NH₂ sequence from HspA were studied by potentiometry, mass spectrometry, circular dichroism and UV-Vis spectroscopy. Ac–CC–NH₂ was used as a reference peptide. The studies have shown that nickel ions form planar complexes with a {2S⁻,N⁻} binding mode. The thiol sulfurs of the –Cys–Cys– motif are also the anchoring sites for Bi³⁺, Zn²⁺ and Cd²⁺ ions. The studied protein fragments have the highest affinity for Bi³⁺ ions. The thermodynamic stability of Ni²⁺ is much higher then that of Zn²⁺.

HspA, a protein crucial for nickel homeostasis in Helicobacter pylori (H. pylori), has a unique histidine- and cysteine-rich domain at the C terminus. In this work, we compared the coordination of nickel (the natural co-factor) and bismuth (inhibitor) to this domain (Ac-ACCHDHKKH-NH₂) and to a reference peptide (Ac-CHCH-NH₂). Potentiometric, CD, UV-Vis spectroscopic and NMR methods have shown that bismuth binds incomparably stronger than nickel; the same data shows the impact of histidines on such a binding. Our results are in good agreement with earlier biological data and suggest that HspA can be a potential target of the bismuth anti-ulcer drug against H. pylori.

Silver is a non-essential element with promising antimicrobial and anticancer properties. This work is a detailed summary of the newest findings on the bioinorganic chemistry of silver, with a special focus on the applications of Ag+ complexes and nanoparticles. The coordination chemistry of silver is given a reasonable amount of attention, summarizing the most common silver binding sites and giving examples of such binding motifs in biologically important proteins. Possible applications of this metal and its complexes in medicine, particularly as antibacterial and antifungal agents and in cancer therapy, are discussed in detail. The most recent data on silver nanoparticles are also summarized.

The aim of this work is to understand the interactions of Zn(II) with Pra1, a zincophore from Candida albicans, one of the most common causes of serious fungal infections in humans. Pra1 is a 299 amino acid protein, secreted from the fungus to specifically bind Zn(II) and deliver it to a transmembrane zinc transporter, Zrt1. We take the first step towards understanding the bioinorganic chemistry of this process, by pointing out the Zn(II) binding sites in Pra1 and understanding the thermodynamics of such interactions. Our approach involves working on model systems (unstructured parts of proteins) in order to identify those regions in Pra1, to which zinc binds with the highest affinity. Mass spectrometry shows the stoichiometry of Zn(II)–peptide complex formation and potentiometric studies give us the partial and overall stability constants for all the formed zinc complexes. NMR clarifies binding sites in the case of doubts. A detailed comparison of these results shows that the C-terminal region of Pra1 binds Zn(II) with the highest affinity, indicating that this region of the zincophore is responsible for the binding of zinc. Such knowledge is an input to the basic bioinorganic chemistry of zinc; it allows us to understand the inorganic biochemistry of zincophores, and it might be a stepping stone towards finding new, fungus specific treatments based on parts of zincophores coupled with antifungal drugs.