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<p> Four stucturally distinct types of macromolecular antifreezes have been previously isolated from the sera of polar marine fish. When the water temperature surrounding these organisms drops below -0.7°C, the freezing point of their bodily fluids, any contact with surrounding ice will nucleate internal ice crystal growth. The antifreeze proteins (AFPs) and antifreeze glycoproteins (AFGPs) synthesized by the fish act to inhibit the growth of existing ice crystals in their sera through direct adsorption to the ice lattice. The α-helical structure of type I AFP from winter flounder has been solved to atomic resolution and its mechanism of ice binding has been proposed. The NMR solution structure of a type III AFP from ocean pout has identified proteins in this class to exist in a β-sandwich conformation, however their mechanism of action remains uncertain.</p> <p> To facilitate the pursuit of an x-ray crystal structure solution, we subcloned the gene for a type III AFP (HPLC6) into pET15b and expressed recombinant His-rHPLC6 AFP in E. coli. Purified rmHPLC6 product has been successfully crystallized, and heavy atom soaks were performed in order to attempt a structure solution by multiple isomorphous replacement. The lone tyrosine in this recombinant AFP has been successfully derivatized in solution with iodine, and the modified protein was crystallized. In order to optimize the measurement of anomalous scattering information, modifications to our data collection system were required. Cryocrystallography techniques were employed to improve the quality of collected data.</p> <p> The expression, purification, crystallization and optimized data collection on an iodine-derivatized type III AFP from ocean pout will be presented here. This work has been instrumental in providing the high quality x-ray data required to solve the crystal structure to atomic resolution. Future examination of the solved structure will promote an increased understanding of the ice-binding mechanism exhibited by this class of proteins.</p> / Thesis / Master of Science (MSc)

An integrated program has been developed to explore the reactivity of 2:1 phyllosilicates (biotite and the clays montmorillonite, hectorite, and nontronite) with respect to acid dissolution using in situ atomic force microscopy (AFM). Three techniques are described which make it possible to fix these minerals and other small particles to a suitable substrate for examination in the fluid cell of the atomic force microscope. A suite of macros has also been developed for the Image SXM image analysis environment which make possible the accurate and consistent measurement of the dimensions of clay particles in a series of AFM images, so that dissolution rates can be measured during a fluid cell experiment. Particles of biotite and montmorillonite were dissolved, and their dissolution rates normalized to their reactive surface area, which corresponds to the area of their edge surfaces (A_e). The A_e-normalized rates for these minerals between pH 1-2 are all ~10E^-8 mol/m²*s, and compare very well to other A_e-normalized dissolution rates in the literature. Differences between the A_e-normalized rates for biotite and the BET-normalized rates (derived from solution chemical studies) found in the literature can be easily explained in terms of the proportion of edge surface area and the formation of leached layers. However, the differences between the A_e-normalized montmorillonite rates and the literature values cannot be explained the same way. Rather, it is demonstrated that rates derived from solution studies of montmorillonite dissolution have been affected by the colloidal behavior of the mineral particles. Finally, the dissolution behavior of hectorite (a trioctahedral smectite) and nontronite ( a dioctahedral smectite) were compared. Based on the differential reactivity of their crystal faces, a model of their surface atomic structures is formulated using Hartman-Perdock crystal growth theory, which explains the observed data if it is assumed that the rate-determining step of the dissolution mechanism is the breaking of connecting bonds between the octahedral and tetrahedral sheets of the mineral structure. / Ph. D.

No / Crystal structure prediction simulations are reported on 5-hydroxymethyl-2-oxazolidinone and 4-hydroxymethyl-2-oxazolidinone to establish the feasibility of predicting the spontaneous resolution of racemates of small organic molecules. It is assumed that spontaneous resolution occurs when the enantiomorph is more stable than the racemic solid. The starting point is a gas phase conformational search to locate all low-energy conformations. These conformations are used to predict the possible crystal structures of 5- and 4-hydroxymethyl-2-oxazolidinone. In both cases, the racemic crystal structure is predicted to have the lowest energy. The energy differences between the lowest-energy racemic solids and the lowest-energy enantiomorphs are 0.2 kcal mol-1 for 5-hydroxymethyl-2-oxazolidinone and 0.9 kcal mol-1 for 4-hydroxymethyl-2-oxazolidinone. In the case of 4-hydroxymethyl-2-oxazolidinone, where the racemic crystal is known to be more stable and the experimental crystal structures of both the racemate and the enantiomorph are available, the simulation results match the observed data. For 5-hydroxymethyl-2-oxazolidinone, where only enantiopure crystals are observed experimentally, the known experimental structure is found 1.6 kcal mol-1 above the lowest-energy predicted structure. This work shows that it is possible to predict whether the racemate of a small chiral molecule can be resolved spontaneously, although further advances in the accuracy of lattice energy calculations are required.

No / A crystal structure prediction (CSP) study of three small, rigid and structurally related organic compounds (differing only in the position and number of methyl groups) is presented. A tailor-made force field (TMFF; a non-transferable force field specific for each molecule) was constructed with the aid of a dispersion-corrected density functional theory method (the hybrid method). Parameters for all energy terms in each TMFF were fitted to reference data generated by the hybrid method. Each force field was then employed during structure generation. The experimentally observed crystal structures of two of the three molecules were found as the most stable crystal packings in the lists of their force-field-optimised structures. A number of the most stable crystal structures were re-optimised with the hybrid method. One experimental crystal structure was still calculated to be the most stable structure, whereas for another compound the experimental structure became the third most stable structure according to the hybrid method. For the third molecule, the experimentally observed polymorph, which was found to be the fourth most stable form using its TMFF, became the second most stable form. Good geometrical agreements were observed between the experimental structures and those calculated by both methods. The average structural deviation achieved by the TMFFs was almost twice that obtained with the hybrid method. The TMFF approach was extended by exploring the accuracy of a more general TMFF (GTMFF), which involved fitting the force-field parameters to the reference data for all three molecules simultaneously. This GTMFF was slightly less accurate than the individual TMFFs but still of sufficient accuracy to be used in CSP. A study of the isostructural relationships between these molecules and their crystal lattices revealed a potential polymorph of one of the compounds that has not been observed experimentally and that may be accessible in a thorough polymorph screen, through seeding, or through the use of a suitable tailor-made additive.

No / A crystal ball? A new method for crystal structure prediction combines a tailor-made force field with a density functional theory method incorporating a van der Waals correction for dispersive interactions. In a blind test, the method predicts the correct crystal structure for all four compounds, one of which is a cocrystal. The picture shows the predicted structure of one of the compounds in green and the experimental structure in blue.

No / Decaprenylphosphoryl-b-d-ribose 20-epimerase (DprE1) is a potential drug target for development of antitubercular agents. Structure based drug discovery approach yielded twenty novel derivatives of benzothiazolylpyrimidine-5-carboxamides (7a–t) which were synthesised by three component one pot reaction involving benzothiazolyl oxobutanamide, thiourea and substituted aromatic benzaldehydes. These derivatives were evaluated for antitubercular activity to determine MIC and compound 7a, 7e, 7f and 7o were found to be potentially active against Mycobacterium tuberculosis (H37Rv). Log P of these compounds was found to be between 2.0 and 3.0 making them suitable for oral dosing. DprE1 selectivity and pharmacokinetic studies were carried out for these compounds of which 7a and 7o were found to be highly selective and bioavailability was found to be above 52% by oral dose. Crystal structure of 7a was studied and molecular packing was determined, it exhibited a triclinic crystal lattice arrangement having hydrogen bonded dimeric arrangement. Drug receptor interactions were studied which exhibited docking in the active site of receptor with hydrogen bonding, hydrophobic interactions, vdW interactions with amino acid residues such as Cys387, Asn385, Lys418, Tyr314, Gln334 and Lys367 respectively. 3D QSAR analysis was carried out by kNN-MFA method to determine and develop theoretical model, best suitable model was found to be based on Simulated Annealing k-Neariest Neighbour Molecular Field Analysis (SA kNN-MFA). The model provided with hydrophobic descriptors in positive side indicating the need of bulky groups, steric and electronegative descriptors in negative coordinates hints with contribution by the electronegative substitutions as favourable and desirable moieties for enhancing the activity. The q2, q2_se and Pred_r2se were found to be 0.5000, 0.6404 and 1.0094 respectively. A pharmacophore model was generated which suggested for necessity of aromatic, aliphatic carbon centre and hydrogen bond donor for development of newer DprE1 selective inhibitors. / Council of Scientific and Industrial Research

No / The Sikhote-Alin (SA) meteorite is an example of a type IIAB octahedrite iron meteorite with ca. 0.5 wt% phosphorus (P) content principally in the form of the siderophilic mineral schreibersite (Fe,Ni)(3)P. Meteoritic in-fall to the early Earth would have added significantly to the inventory of such siderophilic P. Subsequent anaerobic corrosion in the presence of a suitable electrolyte would produce P in a form different to that normally found within endogenous geochemistry which could then be released into the environment. One environment of specific interest includes the low pH conditions found in fumaroles or volcanically heated geothermal waters in which anodic oxidation of Fe metal to ferrous (Fe2+) and ferric (Fe3+) would be coupled with cathodic reduction of a suitable electron acceptor. In the absence of aerobic dioxygen (E-o = +1.229 V), the proton would provide an effective final electron acceptor, being converted to dihydrogen gas (E-o = 0 V). Here we explore the hydrothermal modification of sectioned samples of the Sikhote-Alin meteorite in which siderophilic P-phases are exposed. We report on both, (i) simulated volcanic conditions using low pH distilled water and (ii) geothermally heated sub-glacial fluids from the northern Kverkfjoll volcanic region of the Icelandic Vatnajokull glacier. A combination of X-ray photoelectron spectroscopy (XPS) and electrochemical measurements using the scanning Kelvin probe (SKP) method reveals that schreibersite inclusions are significantly less susceptible to anodic oxidation than their surrounding Fe-Ni matrix, being some 550 mV nobler than matrix material. This results in preferential corrosion of the matrix at the matrix-inclusion boundary as confirmed using topological mapping via infinite focus microscopy and chemical mapping through Raman spectroscopy. The significance of these observations from a chemical perspective is that electrochemically noble inclusions such as schreibersite are likely to have been released into the geological environment through an undermining corrosion of the surrounding matrix, thus affording localised sources of available water-soluble, chemically reactive P in the form of H-phosphite [H2PO3-, Pi(III) as determined by P-31 NMR spectroscopy]. This compound has been shown to have considerable prebiotic chemical potential as a source of condensed P-oxyacids. Here we demonstrate that Pi(III) resulting from the hydrothermal modification of Sikhote- Alin by sub-glacial geothermal fluids can be readily dehydrated into the condensed P-oxyacid pyrophosphite [H2P2O52-, PPi(III)] by dry-heating under mild (85 degrees C) conditions. The potential significance of this latter condensed P-compound for prebiotic chemistry is discussed in the light of its modified chemical properties compared to pyrophosphate [H2P2O72-, PPi(V)].

Yes / Derivatives of fulgides have been shown to have interesting photochromic properties. We have synthesised a number of such derivatives and have found, in some cases, that crystals can be made to change colour on crushing, a phenomenon we have termed "tribochromism". We have studied a number of derivatives by X-ray crystallography, to see if the colour is linked to molecular structure or crystal packing, or both, and our structural results have been supported by calculation of molecular and lattice energies. A number of 5-dicyanomethylene-4-diphenylmethylene-3-disubstitutedmethylene-tetrahydrofuran-2 -one compounds have been prepared and structurally characterised. The compounds are obtained as yellow or dark red crystals, or, in one case, both. In two cases where yellow crystals were obtained, we found that crushing the crystals gave a deep red powder. Structure determinations, including those of the one compound which gave both coloured forms, depending on crystallisation conditions, showed that the yellow crystals contained molecules in which the structure comprised a folded conformation at the diphenylmethylene site, whilst the red crystals contained molecules in a twisted conformation at this site. Lattice energy and molecular conformation energies were calculated for all molecules, and showed that the conformational energy of the molecule in structure IIIa (yellow) is marginally higher, and the conformation thus less stable, than that of the molecule in structure IIIb (red). However, the van der Waals energy for crystal structure IIIa, is slightly stronger than that of structure IIIb - which may be viewed as a hint of a metastable packing preference for IIIa, overcome by the contribution of a more stabilising Coulomb energy to the overall more favourable lattice energy of structure IIIb. Our studies have shown that the crystal colour is correlated with one of two molecular conformations which are different in energy, but that the less stable conformation can be stabilised by its host crystal lattice. Graphical abstractGraphical representation of the structural and colour change in the tribochromic compound (III).