Regulations of organism by materials: a new understanding of biological inorganic chemistry.

Chemical biology generally highlights the modulation or control of life processes using chemical molecules. However, the rapid development of materials' science has resulted in the increasing application of various functional materials in biological regulation. More importantly, the state of art of creating the integration of materials, either the inorganic or organic matrices, with living organisms has opened a window of opportunity to add the multiplex function to organisms. In this review, we suggest a new concept of materials' biology that refers to promoting functional evolution of living organisms using material-based modification of structures, functions, and behaviors of biological organisms, which could change the modification of organisms from the current molecular-level regulation to materials' level. Thus, this review focuses on the recent achievements of material-based modification of organisms that evolves the biological function of cells, bacteria, and viruses using biomimetic strategies. The bioinspired strategies for material-based modification, including layer-by-layer, biomimetic mineralization, interfacial reactive deposition, etc., are briefly introduced. Furthermore, the interaction between materials and organisms has performed a broad function that is not retained by organisms at their native state, which results in the applications in structural support, protection, environment control, energy, vaccine improvement, and cancer treatment. The significance of material-based regulations of organism is to use rationally designed materials to endow new physiological functions to organisms, which provides another perspective to understand biological inorganic chemistry. The roles of materials in chemical regulations of biology are highlighted. New characteristics as well as functions can be achieved by integration the rationally designed materials onto/into living organisms, following material-assisted biological improvement/evolution.

Rational design of substrate binding pockets in polyphosphate kinase for use in cost-effective ATP-dependent cascade reactions.

Adenosine-5'-triphosphate (ATP) is the energy equivalent of the living system. Polyphosphate (polyP) is the ancient energy storage equivalent of organisms. Polyphosphate kinases (PPKs) catalyze the polyP formation or ATP formation, to store energy or to regenerate ATP, respectively. However, most PPKs are active only in the presence of long polyPs, which are more difficult and more expensive to generate than the short polyPs. We investigated the PPK preference towards polyPs by site-directed mutagenesis and computational simulation, to understand the mechanism and further design enzymes for effective ATP regeneration using short polyPs for in vitro cascade reactions, which are highly desired for research and applications. The results suggest that the short polyPs inhibit PPK by blocking the ADP-binding pocket. Structural comparison between PPK (Corynebacterium glutamicum) and PPK (Sinorhizobium meliloti) indicates that three amino acid residues, i.e., lysine, glutamate, and threonine, are involved in the activity towards short polyP by fixing the adenosine group of ADP in between the subunits of the dimer, while the terminal phosphate group of ADP still offers an active site, which presents a binding pocket for ADP. A proposed triple mutant PPK (SMc02148-KET) demonstrates significant activity towards short polyP to form ATP from ADP. The obtained high glutathione titer (38.79 mM) and glucose-6-phosphate titer (87.35 mM) in cascade reactions with ATP regeneration using the triple mutant PPK (SMc02148-KET) reveal that the tailored PPK establishes the effective ATP regeneration system for ATP-dependent reactions.

Efficient biomass pretreatment using ionic liquids derived from lignin and hemicellulose.

Ionic liquids (ILs), solvents composed entirely of paired ions, have been used in a variety of process chemistry and renewable energy applications. Imidazolium-based ILs effectively dissolve biomass and represent a remarkable platform for biomass pretreatment. Although efficient, imidazolium cations are expensive and thus limited in their large-scale industrial deployment. To replace imidazolium-based ILs with those derived from renewable sources, we synthesized a series of tertiary amine-based ILs from aromatic aldehydes derived from lignin and hemicellulose, the major by-products of lignocellulosic biofuel production. Compositional analysis of switchgrass pretreated with ILs derived from vanillin, p-anisaldehyde, and furfural confirmed their efficacy. Enzymatic hydrolysis of pretreated switchgrass allowed for direct comparison of sugar yields and lignin removal between biomass-derived ILs and 1-ethyl-3-methylimidazolium acetate. Although the rate of cellulose hydrolysis for switchgrass pretreated with biomass-derived ILs was slightly slower than that of 1-ethyl-3-methylimidazolium acetate, 90-95% glucose and 70-75% xylose yields were obtained for these samples after 72-h incubation. Molecular modeling was used to compare IL solvent parameters with experimentally obtained compositional analysis data. Effective pretreatment of lignocellulose was further investigated by powder X-ray diffraction and glycome profiling of switchgrass cell walls. These studies showed different cellulose structural changes and differences in hemicellulose epitopes between switchgrass pretreatments with the aforementioned ILs. Our concept of deriving ILs from lignocellulosic biomass shows significant potential for the realization of a "closed-loop" process for future lignocellulosic biorefineries and has far-reaching economic impacts for other IL-based process technology currently using ILs synthesized from petroleum sources.

Electrophoretic separation techniques and their hyphenation to mass spectrometry in biological inorganic chemistry.

Electrophoretic methods have been widely applied in research on the roles of metal complexes in biological systems. In particular, CE, often hyphenated to a sensitive MS detector, has provided valuable information on the modes of action of metal-based pharmaceuticals, and more recently new methods have been added to the electrophoretic toolbox. The range of applications continues to expand as a result of enhanced CE-to-MS interfacing, with sensitivity often at picomolar level, and evolved separation modes allowing for innovative sample analysis. This article is a followup to previous reviews about CE methods in metallodrug research (Electrophoresis, 2003, 24, 2023-2037; Electrophoresis, 2007, 28, 3436-3446; Electrophoresis, 2012, 33, 622-634), also providing a comprehensive overview of metal species studied by electrophoretic methods hyphenated to MS. It highlights the latest CE developments, takes a sneak peek into gel electrophoresis, traces biomolecule labeling, and focuses on the importance of early-stage drug development.

High-frequency and high-field electron paramagnetic resonance (HFEPR): a new spectroscopic tool for bioinorganic chemistry.

This minireview describes high-frequency and high-field electron paramagnetic resonance (HFEPR) spectroscopy in the context of its application to bioinorganic chemistry, specifically to metalloproteins and model compounds. HFEPR is defined as frequencies above ~100 GHz (i.e., above W-band) and a resonant field reaching 25 T and above. The ability of HFEPR to provide high-resolution determination of g values of S = 1/2 is shown; however, the main aim of the minireview is to demonstrate how HFEPR can extract spin Hamiltonian parameters [zero-field splitting (zfs) and g values] for species with S > 1/2 with an accuracy and precision unrivalled by other physical methods. Background theory on the nature of zfs in S = 1, 3/2, 2, and 5/2 systems is presented, along with selected examples of HFEPR spectroscopy of each that are relevant to bioinorganic chemistry. The minireview also provides some suggestions of specific systems in bioinorganic chemistry where HFEPR could be rewardingly applied, in the hope of inspiring workers in this area.

The bioinorganic chemistry of apoptosis: potential inhibitory zinc binding sites in caspase-3.

Zn(2+) inhibits the action of several of the caspases and thus may act as a regulator of apoptosis. Reversal of this inhibition is one possible approach for the development of apoptosis-based therapies. Few studies describe the molecular details of the Zn(2+)-caspase interaction, the understanding of which is essential for the success of any therapeutic strategies. Enzyme kinetics and biophysical studies have shown that the inhibition is of mixed type with prominent (ca. 60 % of inhibition) uncompetitive characteristics and an IC50 of 0.8 µM under the conditions used. Fluorescence-based techniques confirmed that, during inhibition in the sub-micromolar range, substrate binding remains unaffected. A new zinc binding site composed of the catalytic histidine and a nearby methionine residue, rather than the catalytic histidine and cysteine dyad, is proposed based on the experimental observations. DFT models were used to demonstrate that the proposed site could be the preferred inhibitory zinc binding site.

NMR spectroscopy in bioinorganic chemistry.

Multinuclear and multidimensional nuclear magnetic resonance (NMR) spectroscopy is applied in our groups to gain insights into the role of metal ions for the function and structure of large biomolecules. Specifically, NMR is used i) to investigate how metal ions bind to nucleic acids and thereby control the folding and structure of RNAs, ii) to characterize how metal ions are able to stabilize modified nucleic acids to be used as potential nanowires, and iii) to characterize the formation, structure, and role of the diverse metal clusters within plant metallothioneins. In this review we summarize the various NMR experiments applied and the information obtained, demonstrating the important and fascinating part NMR spectroscopy plays in the field of bioinorganic chemistry.

Specific incorporation of chalcogenide bridge atoms in molybdenum/tungsten-iron-sulfur single cubane clusters.

An extensive series of heterometal-iron-sulfur single cubane-type clusters with core oxidation levels [MFe(3)S(3)Q](3+,2+) (M = Mo, W; Q = S, Se) has been prepared by means of a new method of cluster self-assembly. The procedure utilizes the assembly system [((t)Bu(3)tach)M(VI)S(3)]/FeCl(2)/Na(2)Q/NaSR in acetonitrile/THF and affords product clusters in 30-50% yield. The trisulfido precursor acts as a template, binding Fe(II) under reducing conditions and supplying the MS(3) unit of the product. The system leads to specific incorporation of a µ(3)-chalcogenide from an external source (Na(2)Q) and affords the products [((t)Bu(3)tach)MFe(3)S(3)QL(3)](0/1-) (L = Cl(-), RS(-)), among which are the first MFe(3)S(3)Se clusters prepared. Some 16 clusters have been prepared, 13 of which have been characterized by X-ray structure determinations including the incomplete cubane [((t)Bu(3)tach)MoFe(2)S(3)Cl(2)(µ(2)-SPh)], a possible trapped intermediate in the assembly process. Comparisons of structural and electronic features of clusters differing only in atom Q at one cubane vertex are provided. In comparative pairs of complexes differing only in Q, placement of one selenide atom in the core increases core volumes by about 2% over the Q = S case, sets the order Q = Se > S in Fe-Q bond lengths and Q = S > Se in Fe-Q-Fe bond angles, causes small positive shifts in redox potentials, and has an essentially nil effect on (57)Fe isomer shifts. Iron mean oxidation states and charge distributions are assigned to most clusters from isomer shifts. ((t)Bu(3)tach = 1,3,5-tert-butyl-1,3,5-triazacyclohexane).

Metal-sulfur valence orbital interaction energies in metal-dithiolene complexes: determination of charge and overlap interaction energies by comparison of core and valence ionization energy shifts.

The electronic interactions between metals and dithiolenes are important in the biological processes of many metalloenzymes as well as in diverse chemical and material applications. Of special note is the ability of the dithiolene ligand to support metal centers in multiple coordination environments and oxidation states. To better understand the nature of metal-dithiolene electronic interactions, new capabilities in gas-phase core photoelectron spectroscopy for molecules with high sublimation temperatures have been developed and applied to a series of molecules of the type Cp(2)M(bdt) (Cp = η(5)-cyclopentadienyl, M = Ti, V, Mo, and bdt = benzenedithiolato). Comparison of the gas-phase core and valence ionization energy shifts provides a unique quantitative energy measure of valence orbital overlap interactions between the metal and the sulfur orbitals that is separated from the effects of charge redistribution. The results explain the large amount of sulfur character in the redox-active orbitals and the 'leveling' of oxidation state energies in metal-dithiolene systems. The experimentally determined orbital interaction energies reveal a previously unidentified overlap interaction of the predominantly sulfur HOMO of the bdt ligand with filled π orbitals of the Cp ligands, suggesting that direct dithiolene interactions with other ligands bound to the metal could be significant for other metal-dithiolene systems in chemistry and biology.

Cubane-type Fe4S4 clusters with chiral thiolate ligation: formation by ligand substitution, detection of intermediates by 1H NMR, and solid state structures including spontaneous resolution upon crystallization.

Cubane-type clusters [Fe(4)S(4)(SR*)(4)](2-) containing chiral thiolate ligands with R* = CH(Me)Ph (1), CH(2)CH(Me)Et (2), and CH(2)CH(OH)CH(2)OH (3) have been prepared by ligand substitution in the reaction systems [Fe(4)S(4)(SEt)(4)]/R*SH (1-3, acetonitrile) and [Fe(4)S(4)Cl(4)](2-)/NaSR*(3, Me(2)SO). Reactions with successive equivalents of thiol or thiolate generate the species [Fe(4)S(4)L(4-n)(SR*)(n)](2-) (L = SEt, Cl) with n = 1-4. Clusters 1 and 2 were prepared with racemic thiols leading to the possible formation of one enantiomeric pair (n = 1) and seven diastereomers and their enantiomers (n = 2-4). Reactions were monitored by isotropically shifted (1)H NMR spectra in acetonitrile or Me(2)SO. In systems affording 1 and 2 as final products, individual mixed-ligand species could not be detected. However, crystallization of (Et(4)N)(2)[1] afforded 1-[SS(RS)(RS)] in which two sites are disordered because of occupancy of R and S ligands. Similarly, (Et(4)N)(2)[2] led to 2-[SSSS], a consequence of spontaneous resolution upon crystallization. The clusters 3-[RRRR] and 3-[SSSS] were obtained from enantiomerically pure thiols. Successive reactions lead to detection of species with n = 1-4 by appearance of four pairs of diastereotopic SCH(2) signals in both acetonitrile and Me(2)SO reaction systems. Identical spectra were obtained with racemic, R-(-), and S-(+) thiols, indicating that ligand-ligand interactions are too weak to allow detection of diastereomers (e.g., [SSSS] vs [SSRR]). The stability of 3 in Me(2)SO/H(2)O media is described.

Iron(II) vacataporphyrins: a variable annulene conformation inside a regular porphyrin frame.

5,10,15,20-Tetraaryl-21-vacataporphyrin (1), an annulene-porphyrin hybrid containing a butadiene fragment in the macrocycle perimeter, gives paramagnetic iron(II) complexes 2. The porphyrin 1 is devoid of one donor atom of the coordination core; hence, metal ion is bound in the macrocyclic cavity by only three pyrrolic nitrogen atoms. The coordination sphere in 2-X (where X = Cl, Br, I) is completed by a halide anion. The butadiene fragment flexibility and constraints of coordination lead to two stereoisomers with the chain oriented inward (2-i-X) or outward (2-o-X) of the macrocyclic center. Axial halide subtraction (AgBF(4) addition) leads to two new forms differing in the butadiene chain configuration. The (1)H NMR spectra of all complexes show characteristics typical for high-spin iron(II) complexes of porphyrinoids. The dependence of the relaxation times T(1) versus Fe(II)···H distances (estimated by MM+ models) for three of the isomers is in accordance with the in, out, and/or zigzag geometries. The 2-o-X complex is more reactive than 2-i-X and reacts at room temperature with dioxygen to form the iron(II) 21-oxaporphyrin complex, conserving the iron(II) oxidation state. After the addition of imidazole or excess of methanol to a mixture of 2-o-X and 2-i-X, single five-coordinate complexes with out annulene configuration and two axial ligands are formed.

Self-assembly and redox modulation of the cavity size of an unusual rectangular iron thiolate aryldiisocyanide metallocyclophane.

The decarbonylation reaction of ferric carbonyl dicationic [Cp(2)Fe(2)(µ-SEt)(2)(CO)(2)](BF(4))(2) [1(BF(4))(2)] carried out in refluxing acetonitrile affords a binuclear iron-sulfur core complex [Cp(2)Fe(2)(µ-SEt)(2)(CH(3)CN)(2)](BF(4))(2) [2(BF(4))(2)] containing two acetonitrile coordinated ligands. The treatment of 2(BF(4))(2) with 2 equiv of the 1,4-diisocyanobenzene (1,4-CNC(6)H(4)NC) results in the formation of the diisocyanide complex [Cp(2)Fe(2)(µ-SEt)(2)(1,4-CNC(6)H(4)NC)(2)](BF(4))(2) [3(BF(4))(2)]. The rectangular tetranuclear iron thiolate aryldiisocyanide metallocyclophane complex [Cp(4)Fe(4)(µ-SEt)(4)(µ-1,4-CNC(6)H(4)NC)(2)](BF(4))(4) [4(BF(4))(4)] has been synthesized by a self-assembly reaction between equimolar amounts of 2(BF(4))(2) and 1,4-diisocyanobenzene or by a stepwise route involving mixing of a 1:1 molar ratio of complexes 2(BF(4))(2) and 3(BF(4))(2). Chemical reduction of 4(BF(4))(4) by KC(8) was observed to produce the reduction product 4(BF(4))(2). The spectroscopic and electrochemical properties of the iron-sulfur core complexes 1(PF(6))(2), 3(BF(4))(2), 4(BF(4))(4), and 4(BF(4))(2) were determined. Finally, differences between the redox control cavities of rectangular tetranuclear iron thiolate aryldiisocyanide complexes are revealed by a comparison of the X-ray crystallographically determined structures of complexes 4(BF(4))(4) and 4(BF(4))(2).

A perspective essay on the use of Ga3+ as a proxy for Fe3+ in bioinorganic model studies and its successful use for therapeutic purposes.

The use of Ga3+ as a structural mimic for Fe3+ in model bioinorganic investigations is usually based on a common assumption that Ga3+ and Fe3+ should form bioligand complexes of similar stabilities due to their similar charge/radius ratio (z/r). However, the literature survey presented here is contrary to this notion, showing that under laboratory conditions often Ga3+ forms weaker bioligand complexes than Fe3+in aqueous medium. We hypothesize that this is because Ga3+ is more aquaphilic than Fe3+ as suggested by their relative heats of hydration (ΔHhyd). The successful use of Ga3+ as a therapeutic agent is also briefly reviewed, showing this success often stems from the redox inertness as well as different pharmacokinetics of Ga3+ than Fe3+, but similar metabolic pathways as Fe3+ in human serum.

Application of isothermal titration calorimetry in bioinorganic chemistry.

The thermodynamics of metals ions binding to proteins and other biological molecules can be measured with isothermal titration calorimetry (ITC), which quantifies the binding enthalpy (ΔH°) and generates a binding isotherm. A fit of the isotherm provides the binding constant (K), thereby allowing the free energy (ΔG°) and ultimately the entropy (ΔS°) of binding to be determined. The temperature dependence of ΔH° can then provide the change in heat capacity (ΔC (p)°) upon binding. However, ITC measurements of metal binding can be compromised by undesired reactions (e.g., precipitation, hydrolysis, and redox), and generally involve competing equilibria with the buffer and protons, which contribute to the experimental values (K (ITC), ΔH (ITC)). Guidelines and factors that need to be considered for ITC measurements involving metal ions are outlined. A general analysis of the experimental ITC values that accounts for the contributions of metal-buffer speciation and proton competition and provides condition-independent thermodynamic values (K, ΔH°) for metal binding is developed and validated.

Bioinorganic chemistry of open-angle glaucoma: A review.

At present, physical methods of chemical analysis are constantly improving providing large amount of data on elemental composition of organs and tissues. However, only few works describe the correlation (or the potential connection) between the general or local bioelemental imbalances and specific biochemical reactions that are involved in pathogenesis of certain diseases. This review describes primary open-angle glaucoma (POAG) - one of the most common ophthalmic diseases - in terms of elemental chemistry. The authors look into the impact that various subgroups of elements have on passive and active processes of homeostasis regulation and hydrodynamic balance in the eye. Alkaline metals and their analogues (K, Na, Li, Rb, Cs) influence hydrostatics and hydrodynamics by means of both K-Na pumps and osmosis. Alkaline-earth elements and their analogues (Ca, Mg, Sr, Ba, Be) are involved in biomineralization and intercellular interaction in the drainage areas. Chalcophile metals and their analogues (Zn, Cu, Hg, Co, Ni, Cd, Pb, Mo, Sb) regulate redox reactions. They are the cofactors of enzymes that support structural homeostasis of the drainage area. Siderophile metals (Fe, Mn, Cr, Rh) regulate oxidation-reduction reactions, including those associated with limited nutrition of tissues in glaucoma. The role of amphoteric metals and nonmetals (Al, Si, Ga, V, TI, Sn, Ge, Zr, W) in POAG has not been described properly, but they were noted to participate in mineralization. Structure-forming non-metals and their analogues (N, S, Se, As) are directly involved in the formation of protein and non-protein aggregates that prevent aqueous humor outflow. The specific role of phosphorus in the pathogenesis of glaucoma has not been described previously. The authors analyze the involvement of phosphorus in energy-dependent processes of cellular activity, which are aimed at the reprocessing of aggregates that cause aqueous humor retention.

New approaches for medicinal applications of bioinorganic chemistry.

Inorganic and bioinorganic chemistry have made important contributions to medical science and human health in the past half century. Today, metal-containing imaging agents and therapeutics constitute a multi-billion dollar industry. Recent discoveries in bioinorganic chemistry of potential biomedical importance include the use of metal ions as synthetic scaffolds for the preparation of small molecule therapeutics, which opens up a new route to molecular structure and diversity, as well as the examination of metal-organic frameworks as biological imaging and drug delivery agents. These areas represent some of the most recent and still relatively unexplored themes in inorganic and bioinorganic chemistry that might be exciting and fruitful topics of study for the community interested in 'metals in medicine'.

Sintering and robocasting of beta-tricalcium phosphate scaffolds for orthopaedic applications.

beta-Tricalcium phosphate (beta-TCP) scaffolds with designed, three-dimensional (3-D) geometry and mesoscale porosity have been fabricated by direct-write assembly (robocasting) techniques. Concentrated beta-TCP inks with suitable viscoelastic properties were developed to enable the fabrication of the complex 3-D structures. A comprehensive study of the sintering behavior of TCP as a function of the calcium content in the starting powder was also carried out, and the optimal heat treatment for fabricating scaffolds with dense beta-TCP rods has been determined. Such analysis provides clues to controlling the microstructure of the fabricated structures and, therefore, enabling the fabrication by robocasting of TCP scaffolds with tailored performance for bone tissue engineering applications.

Computational bioinorganic chemistry. Part III. The tools of the trade: from high-level ab initio calculations to structural bioinformatics.

Having long focused on the electronic-structural aspects of metalloenzymes and their synthetic models, Abhik is currently exploring a number of synthetic problems related to self-assembly processes, dynamic combinatorial libraries, and fluorine chemistry.