Computational insights into the inhibition of β-haematin crystallization by antimalarial drugs.

During the red blood cell phase of their life cycle, malaria parasites digest their host's haemoglobin, with concomitant release of potentially toxic iron(iii) protoporphyrin IX (FePPIX). The parasites' strategy for detoxification of FePPIX involves its crystallization to haemozoin, such that the build-up of free haem in solution is avoided. Antimalarial drugs of both historical importance and current clinical use are known to be capable of disrupting the growth of crystals of β-haematin, which is the synthetic equivalent of haemozoin.

Direct infrared observation of hydrogen chloride anions in solid argon.

To facilitate direct spectroscopic observation of hydrogen chloride anions (HCl), electron bombardment of CHCl diluted in excess Ar during matrix deposition was used to generate this anion. Subsequent characterization were performed by IR spectroscopy and quantum chemical calculations. Moreover the band intensity of HCl decays slowly when the matrix sample is maintained in the dark for a prolonged time.

Biotransformation and molecular docking studies of aromatase inhibitors.

Bioconversion of the aromatase inhibitor formestane (4-hydroxyandrost-4-ene-3,17-dione) (1) by the fungus Rhizopus oryzae ATCC 11145 resulted in a new minor metabolite 3,5α-dihydroxyandrost-2-ene-4,17-dione (2) and the known 4β,5α-dihydroxyandrostane-4,17-dione (3) as the major product. The structural elucidation and bioactivities of these metabolites are reported herein. Molecular modeling studies of the interactions between these metabolites and the aromatase protein indicated that acidic (D309), basic (R115), polar (T310), aromatic (F134, F221, and W224), and non-polar (I133, I305, A306, V369, V370, L372, V373, M374, and L477) amino acid residues contribute important interactions with the steroidal substrates.

Reply to the 'Comment on "A quantitative definition of hypervalency"' by R. D. Harcourt and T. M. Klapötke, , 2016, , DOI: ; 10.1039/C5SC04866D.

The Lewis and quantum mechanical theories of chemical bonding are compared and contrasted, with a view to clarifying the relationship between Harcourt's 'increased valence' quantum approach and the recently proposed quantitative definition of hypervalency.

When two are better than one: bright phosphorescence from non-stereogenic dinuclear iridium(III) complexes.

A new family of eight dinuclear iridium(iii) complexes has been prepared, featuring 4,6-diarylpyrimidines L(y) as bis-N^C-coordinating bridging ligands. The metal ions are also coordinated by a terminal N^C^N-cyclometallating ligand L(X) based on 1,3-di(2-pyridyl)benzene, and by a monodentate chloride or cyanide. The general formula of the compounds is {IrL(X)Z}2L(y) (Z = Cl or CN).

A quantitative definition of hypervalency.

From the inception of Lewis' theory of chemical bonding, hypervalency has remained a point of difficulty that has not been fully resolved by the currently accepted qualitative definition of this term. Therefore, in this work, a quantitative measure of hypervalency has been developed. The only required input is the atomic charge map, which can be obtained from either quantum calculations or from experiment.

A computational study of ligand binding affinities in iron(III) porphine and protoporphyrin IX complexes.

The search for novel anti-malarial drugs that can disrupt biomineralization of ferriprotoporphyrin IX to haemozoin requires an understanding of the fundamental chemistry of the porphyrin's iron(iii) centre at the water-lipid interface. Towards this end, the binding affinities for a diverse set of 31 small ligands with iron(iii) porphine have been calculated using density functional theory, in the gas phase and also with implicit solvent corrections for both water and n-octanol. In addition, the binding of hydroxide, chloride, acetate, methylamine and water to ferriprotoporphyrin IX has been studied, and very similar trends are observed for the smaller and larger models.

Highly luminescent dinuclear platinum(II) complexes incorporating bis-cyclometallating pyrazine-based ligands: a versatile approach to efficient red phosphors.

A series of luminescent dinuclear platinum(II) complexes incorporating diphenylpyrazine-based bridging ligands (L(n)H2) has been prepared. Both 2,5-diphenylpyrazine (L(2)H2) and 2,3-diphenylpyrazine (L(3)H2) are able to undergo cyclometalation of the two phenyl rings, with each metal ion binding to the two nitrogen atoms of the central heterocycle, giving, after treatment with the anion of dipivaloyl methane (dpm), complexes of formula {Pt(dpm)}2L(n). These compounds are isomers of the analogous complex of 4,6-diphenylpyrimidine (L(1)H2).

A structural and functional model for human bone sialoprotein.

Human bone sialoprotein (BSP) is an essential component of the extracellular matrix of bone. It is thought to be the primary nucleator of hydroxyapatite crystallization, and is known to bind to hydroxyapatite, collagen, and cells. Mature BSP shows extensive post-translational modifications, including attachment of glycans, sulfation, and phosphorylation, and is highly flexible with no specific 2D or 3D structure in solution or the solid state.

A kinetic and theoretical study of the borate catalysed reactions of hydrogen peroxide: the role of dioxaborirane as the catalytic intermediate for a wide range of substrates.

Our recent work has provided new insights into the equilibria and species that exist in aqueous solution at different pHs for the boric acid - hydrogen peroxide system, and the role of these species in oxidation reactions. Most recently, (M. C.

Dioxaborirane: a highly reactive peroxide that is the likely intermediate in borate catalysed electrophilic reactions of hydrogen peroxide in alkaline aqueous solution.

This paper reports on a kinetic and theoretical study into the borate mediated reaction of dimethyl sulfide with hydrogen peroxide in both acid and alkaline conditions. At high pH, whilst the kinetic data is consistent with the catalytic species being monoperoxoborate, formed from the rapid equilibrium between hydrogen peroxide and boric acid, DFT calculations show that this species is in fact less reactive than hydrogen peroxide, requiring us to seek an alternative catalytic mechanism. DFT provides an important insight for this, showing that although boric acid and peroxoboric acid are primarily Lewis acids, they can exhibit a small degree of Brønsted acidity, allowing, respectively, the B(O)(OH)(2)(-) and HOOB(OH)(O)(-) anions to exist in small concentrations.

Estimation of boiling points using density functional theory with polarized continuum model solvent corrections.

An empirical method for estimation of the boiling points of organic molecules based on density functional theory (DFT) calculations with polarized continuum model (PCM) solvent corrections has been developed. The boiling points are calculated as the sum of three contributions. The first term is calculated directly from the structural formula of the molecule, and is related to its effective surface area.

Highly luminescent mixed-metal Pt(II)/Ir(III) complexes: bis-cyclometalation of 4,6-diphenylpyrimidine as a versatile route to rigid multimetallic assemblies.

The proligand 4,6-di-(4-tert-butylphenyl)pyrimidine LH(2) can undergo cycloplatination with K(2)PtCl(4) at one of the two aryl rings to give, after treatment with sodium acetylacetonate, a mononuclear complex Pt(N^C-LH)(acac) (denoted Pt). If an excess of K(2)PtCl(4) is used, a dinuclear complex of the form [Pt(acac)](2){μ-(N^C-L-N^C)} (Pt(2)) is obtained instead, where the pyrimidine ring acts as a bridging unit. Alternatively, the mononuclear complex can undergo cyclometalation with a different metal ion.

Estimation of the pKa values of water ligands in transition metal complexes using density functional theory with polarized continuum model solvent corrections.

The deprotonation energies of the water ligands in a set of 40 d-block metal complexes have been calculated using density functional theory with polarized continuum model solvent corrections. The complexes include 13 aqua ions [M(OH(2))(n)](2+/3+) and a variety of aqua complexes with organic co-ligands, whose experimental pK(a) values have been reported in the literature. For comparison, the deprotonation energies of a set of 60 organic and inorganic molecules with experimental pK(a) values ranging from -25 (HSbF(6)) to +52 (C(2)H(6)) have also been calculated.

The action of the bacterial toxin, microcin B17, on DNA gyrase.

Microcin B17 (MccB17) is a peptide-based bacterial toxin that targets DNA gyrase, the bacterial enzyme that introduces supercoils into DNA. The site and mode of action of MccB17 on gyrase are unclear. We review what is currently known about MccB17-gyrase interactions and summarise approaches to understanding its mode of action that involve modification of the toxin.

The use of quantum molecular calculations to guide a genetic algorithm: a way to search for new chemistry.

The process of gene-based molecular evolution has been simulated in silico by using massively parallel density functional theory quantum calculations, coupled with a genetic algorithm, to test for fitness with respect to a target chemical reaction in populations of genetically encoded molecules. The goal of this study was the identification of transition-metal complexes capable of mediating a known reaction, namely the cleavage of N(2) to give the metal nitride. Each complex within the search space was uniquely specified by a nanogene consisting of an eight-digit number.

Evidence for a dynamic role for homocitrate during nitrogen fixation: the effect of substitution at the alpha-Lys426 position in MoFe-protein of Azotobacter vinelandii.

Although it is generally accepted that the active site of nitrogenase is located on the FeMo-cofactor, the exact site(s) of N2 binding and reduction remain the subject of continuing debate, with both molybdenum and iron atoms being suggested as key players. The current consensus favours binding of acetylene and some other non-biologically relevant substrates to the central iron atoms of the FeMo-cofactor [Dos Santos, Igarashi, Lee, Hoffman, Seefeldt and Dean (2005) Acc. Chem.

A RhoGDP dissociation inhibitor spatially regulates growth in root hair cells.

Root hairs are cellular protuberances extending from the root surface into the soil; there they provide access to immobile inorganic ions such as phosphate, which are essential for growth. Their cylindrical shape results from a polarized mechanism of cell expansion called tip growth in which elongation is restricted to a small area at the surface of the hair-forming cell (trichoblast) tip. Here we identify proteins that spatially control the sites at which cell growth occurs by isolating Arabidopsis mutants (scn1) that develop ectopic sites of growth on trichoblasts.

SapT, a lanthionine-containing peptide involved in aerial hyphae formation in the streptomycetes.

The developmentally complex soil microbe Streptomyces tendae secretes a hydrophobic peptide that restored to developmental mutants of S. coelicolor the ability to raise aerial hyphae. The S.

The antifolate activity of tea catechins.

A naturally occurring gallated polyphenol isolated from green tea leaves, (-)-epigallocatechin gallate (EGCG), has been shown to be an inhibitor of dihydrofolate reductase (DHFR) activity in vitro at concentrations found in the serum and tissues of green tea drinkers (0.1-1.0 micromol/L).

Structure-function analysis of cf-9, a receptor-like protein with extracytoplasmic leucine-rich repeats.

The tomato (Lycopersicon pimpinellifolium) resistance protein Cf-9 belongs to a large class of plant proteins with extracytoplasmic Leu-rich repeats (eLRRs). eLRR proteins play key roles in plant defense and development, mainly as receptor-like proteins or receptor-like kinases, conferring recognition of various pathogen molecules and plant hormones. We report here a large-scale structure-function analysis of an eLRR protein.

Epitope tagging of legume root nodule extensin modifies protein structure and crosslinking in cell walls of transformed tobacco leaves.

Root nodule extensins (RNEs) are highly glycosylated plant glycoproteins localized in the extracellular matrix of legume tissues and in the lumen of Rhizobium-induced infection threads. In pea and other legumes, a family of genes encode glycoproteins of different overall length but with the same basic composition. The predicted polypeptide sequence reveals repeating and alternating motifs characteristic of extensins and arabinogalactan proteins.

A patch of surface-exposed residues mediates negative regulation of immune signaling by tomato Pto kinase.

Tomato (Lycopersicon esculentum) Pto kinase specifically recognizes the Pseudomonas effector proteins AvrPto and AvrPtoB, leading to induction of defense responses and hypersensitive cell death. Structural modeling of Pto combined with site-directed mutagenesis identified a patch of surface-exposed residues required for native regulation of signaling. Mutations in this area resulted in constitutive gain-of-function (CGF) forms of Pto that activated AvrPto-independent cell death via the cognate signaling pathway.

The SapB morphogen is a lantibiotic-like peptide derived from the product of the developmental gene ramS in Streptomyces coelicolor.

SapB is a morphogenetic peptide that is important for aerial mycelium formation by the filamentous bacterium Streptomyces coelicolor. Production of SapB commences during aerial mycelium formation and depends on most of the genes known to be required for the morphogenesis of aerial hyphae. Furthermore, the application of purified SapB to mutants blocked in morphogenesis restores their capacity to form aerial hyphae.

An atomic level model for the interactions of molybdenum nitrogenase with carbon monoxide, acetylene, and ethylene.

A combination of density functional theory and molecular mechanics calculations has been used to study the possible interactions of CO, C(2)H(2), and C(2)H(4) with the central Fe and terminal Mo sites of the iron-molybdenum cofactor of nitrogenase. The most favorable binding mode for CO on the central section of the FeMoco appears to be end-on to a single Fe and results in a change from high to low spin for the ligating Fe atom. If a coordination site for CO is available on the Mo, this becomes the preferred CO binding site.