How Many O-Donor Groups in Enterobactin Does It Take to Bind a Metal Cation?

The E. coli siderophore enterobactin, the strongest FeIII chelator known to date, forms hexacoordinate complexes with SiIV , GeIV , and TiIV . Synthetic protocols have been developed to prepare non-symmetric enterobactin analogues with varying denticities. Various benzoic acid residues were coupled to the macrocyclic lactone to afford a diverse library of ligands. These enterobactin analogues were bound to SiIV , GeIV , and TiIV , and the complexes were investigated through experimental and computational techniques. The binding behavior of the synthesized chelators enabled assessment of the contribution of each of the phenolic hydroxy groups in enterobactin to metal-ion complexation. It was found that at least four O-donors are needed for enterobactin derivatives to act as metal binders. Density functional theory calculations indicate that the strong binding behavior of enterobactin can be ascribed to a diminished translational entropy penalty, a common feature of the chelate effect, coupled with the structural arrangement of the three catechol moieties, which allows the triseryl base to be installed without distorting the preferred local metal-binding geometry of the catecholate ligands.

Factors Affecting the Production of Aromatic Immonium Ions in MALDI 157 nm Photodissociation Studies.

Immonium ions are commonly observed in the high energy fragmentation of peptide ions. In a MALDI-TOF/TOF mass spectrometer, singly charged peptides photofragmented with 157 nm VUV light yield a copious abundance of immonium ions, especially those from aromatic residues. However, their intensities may vary from one peptide to another. In this work, the effect of varying amino acid position, peptide length, and peptide composition on immonium ion yield is investigated. Internal immonium ions are found to have the strongest intensity, whereas immonium ions arising from C-terminal residues are the weakest. Peptide length and competition among residues also strongly influence the immonium ion production. Quantum calculations provide insights about immonium ion structures and the fragment ion conformations that promote or inhibit immonium ion formation.

A comparison between QM/MM and QM/QM based fitting of condensed-phase atomic polarizabilities.

Recently we reported a combined QM/MM approach to estimate condensed-phase values of atomic polarizabilities for use in (bio)molecular simulation. The setup relies on a MM treatment of the solvent when determining atomic polarizabilities to describe the response of a QM described solute to its external electric field. In this work, we study the effect of using alternative descriptions of the solvent molecules when evaluating atomic polarizabilities of a methanol solute. In a first step, we show that solute polarizabilities are not significantly affected upon substantially increasing the MM dipole moments towards values that are typically reported in literature for water solvent molecules. Subsequently, solute polarization is evaluated in the presence of a QM described solvent (using the frozen-density embedding method). In the latter case, lower oxygen polarizabilities were obtained than when using MM point charges to describe the solvent, due to introduction of Pauli-repulsion effects.

Understanding intrinsically irreversible, non-Nernstian, two-electron redox processes: a combined experimental and computational study of the electrochemical activation of platinum(IV) antitumor prodrugs.

Six-coordinate Pt(IV)-complexes are prominent prodrug candidates for the treatment of various cancers where, upon two-electron reduction and loss of two axial ligands, they form more familiar, pharmacologically active four-coordinate Pt(II) drugs. A series of electrochemical experiments coupled with extensive density functional calculations has been employed to elucidate the mechanism for the two-electron reduction of Pt(IV)(NH3)2Cl2L2 to Pt(II)(NH3)2Cl2 (L = CH3COO(-), 1; L = CHCl2COO(-), 2; L = Cl(-), 3). A reliable estimate for the normal reduction potential E(o) is derived for the electrochemically irreversible Pt(IV) reduction and is compared directly to the quantum chemically calculated reduction potentials. The process of electron transfer and Pt-L bond cleavage is found to occur in a stepwise fashion, suggesting that a metastable six-coordinate Pt(III) intermediate is formed upon addition of a single electron, and the loss of both axial ligands is associated with the second electron transfer. The quantum chemically calculated reduction potentials are in excellent agreement with experimentally determined values that are notably more positive than peak potentials reported previously for 1-3.

Binary role of an ylide in formation of a terminal methylidene complex of niobium.

The first structurally characterized niobium(v) complex possessing a terminal methylidene ligand is reported in high yield from the reaction of [(Ar'O)2Nb(CH3)2Cl] (Ar' = (2,6-CHPh2)2-4-tBu-C6H2) and two equivalents of H2CPPh3.

Synthesis and structural characterization of hexacoordinate silicon, germanium, and titanium complexes of the E. coli siderophore enterobactin.

The E. coli siderophore enterobactin, one of the strongest Fe(III) chelators known to date, is also capable of binding Si(IV) under physiological conditions. We report on the synthesis and structural characterization of the tris(catecholate) Si(IV) -enterobactin complex and its Ge(IV) and Ti(IV) analogues. Comparative structural analysis, supported by quantum-chemical calculations, reveals the correlation between the ionic radius and the structural changes in enterobactin upon complexation.

The role of protein plasticity in computational rationalization studies on regioselectivity in testosterone hydroxylation by cytochrome P450 BM3 mutants.

Recently, it was found that mutations in the binding cavity of drug-metabolizing Cytochrome P450 BM3 mutants can result in major changes in regioselectivity in testosterone (TES) hydroxylation. In the current work, we report the intrinsic reactivity of TES' C-H bonds and our attempts to rationalize experimentally observed changes in TES hydroxylation using a protein structure-based in silico approach, by setting up and employing a combined Molecular Dynamics (MD) and ligand docking approach to account for the flexibility and plasticity of BM3 mutants. Using this approach, about 100,000 TES binding poses were obtained per mutant. The predicted regioselectivity in TES hydroxylation by the mutants was found to be in disagreement with experiment. As revealed in a detailed structural analysis of the obtained docking poses, this disagreement is due to limitations in correctly scoring hydrogen-bonding and steric interactions with specific active-site residues, which could explain the experimentally observed trends in regioselectivity in TES hydroxylation.