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In the absence of X-ray structure of L-type Ca²⁺ channel (LCC), we have built a homology model of LCC based on the crystal structure of KcsA channel and have performed a series 0° docking simulations. The search for lowest-energy conformations was performed by the Monte Carlo energy-minimization method. To obtain the conformation with the lowest energy where dihydropyridine (DHP) ligand forms optimal contacts with the DHP-sensing residues of the channel, we have tested different sequence alignments between KcsA and LCC, and have docked the ligand inside the pore of the channel as well as into the interface between repeats IIIS5-IIIS6-IVS6. The LCC ligand tetrandrine was used during the studies of the selectivity filter of the channel. Conformational studies of the drug and its interaction with Ca²⁺ ions in a non-polar solution were performed by NMR spectroscopy. These experiments have demonstrated the binding of Ca²⁺ ions to the ligand. In the model based on the alignment proposed by Lipkind and Fozzard (2000), the DHP ligand nifedipine fits inside the pore and forms favorable contacts with several hydrophobic DHP-sensing residues, and forms hydrogen bonds with conserved tyrosines in repeats HI and IV. These interactions stabilize the portside-down docking mode of nifedipine, in which this blocker exposes its hydrophobic methoxy group to the bracelet of hydrophobic residues forming the gate of the channel near the crossing of the bundle of helices. The stabilizes the closed state of the channel. In contrast, the agonist has the hydrophilic group at its portside. The favorable interaction of this group with hydrated Ca²⁺ ion facilitates its permeation through hydrophobic gate. We have simulated the passage of the hydrated ion along the pore with the agonist bound inside and determined several residues crucial for this passage. The role of these residues can be tested experimentally. / Thesis / Master of Science (MSc)

Research into inorganic supramolecular chemistry is burgeoning, in particular that which focuses on the formation of capsular molecules and the effects that these unique environments have on catalytic reactions. With the aim of producing new ligand designs that could not only support reactive metals, but also partake in supramolecular aggregation to provide a capsular microenvironment, new tripodal ligands and wide span imines and amines have been synthesised. Furthermore, the exploitation of hydrogen-bonding motifs formed through pyrrole-imine tautomerisation upon metallation of these ligands has been explored, with the aim of enhancing reactivity and stabilising reactive intermediates. In Chapter one, the concept of covalent and non-covalent capsules is introduced, and includes the different aspects affecting the encapsulation of molecules and their use as nanoreactors. The use of secondary interactions, e.g. hydrogen-bonding in metal complexes of tetrapodal and tripodal ligands is discussed. Chapter two describes the synthesis of a tripodal pyrrole-imine ligand and the formation of its multi-metallic complexes of Group one metals, transition metal and the f-block elements. The complete and partial tautomerisation of this ligand upon metal complexation is also examined. In Chapter three, the formation of hangman complexes of the tripodal pyrrole-imine ligand is described and is extrapolated to the chemistry of a new pyrrole-amide ligand. The synthesis of this latter ligand and its properties with regards to anion binding are also explored. Chapter four describes the formation of wide span diamine and diimine ligands and their propensity to form adducts with cobalt and zinc chlorometallates and unusual multimetallic palladium complexes. The final conclusions of the work presented in this thesis are drawn in Chapter five. Chapter six presents experimental details and characterising data for all of the new compounds presented in this thesis.

Thermolysis of CoRu(CO)7(m -PPh2) (1) in refluxing 1,2-dichloroethane in the presence of the diphosphine ligands 2,3-bis(diphenylphosphino)maleic anhydride (bma) and 4,5-bis(diphenylphosphino)-4-cyclopenten-1,3-dione (bpcd) furnishes the new mixed-metal complexes CoRu(CO)4(μ -P-P)(μ -PPh2) [where P-P = bma (3); bpcd (6)], along with trace amounts of the known complex CoRu(CO)6(PPh3)(μ -PPh2) (4). The requisite pentacarbonyl intermediates CoRu(CO)5(μ -P-P)(μ -PPh2) [where P-P = bma (2); bpcd (5)] have been prepared by separate routes and studied for their conversion to CoRu(CO)4(μ -P-P)(μ -PPh2). The complexes 2/3 and 5/6 have been isolated and fully characterized in solution by IR and NMR spectroscopy. The kinetics for the conversion of 2→3 and of 5→6 were measured by IR spectroscopy in chlorobenzene solvent. On the basis of the first-order rate constants, CO inhibition, and the activation parameters, a mechanism involving dissociative CO loss as the rate-limiting step is proposed. The solid-state structure of CoRu(CO)4(μ -bma)(μ -PPh2) (3) reveals that the two PPh2 groups are bound to the ruthenium center while the maleic anhydride π bond is coordinated to the cobalt atom. Thermolysis of the cluster Ru3(CO)12 with the bis(phosphine)hydrazine ligand (MeO)2PN(Me)N(Me)P(OMe)2 (dmpdmh) in toluene at 75°C furnishes the known clusters Ru4(CO)12[μ -N(Me)N(Me)] (9) and Ru3(CO)11[P(OMe)3] (10), in addition to the new cluster Ru3(CO)10(dmpdmh) (8) and the phosphite-tethered cluster Ru3(CO)9[μ -P(OMe)3] (11). The simple substitution product Ru3(CO)10(dmpdmh), a logical intermediate to clusters 9-11, was synthesized by treating Ru3(CO)12 and dmpdmh with Me3NO in CH2Cl2 at room temperature, and independent thermolysis reactions using cluster 8 were shown to yield clusters 9-11. The tetrahedrane cluster FeCo2(CO)9(μ3-S) reacts with the redox-active ligand 4,5-bis(diphenylphosphino)-4-cyclopenten-1,3-dione (bpcd) to give the disubstituted cluster FeCo2(CO)7(bpcd)(μ3-S) as the sole product. This diphosphine-substituted cluster contains a cobalt-bound, chelating bpcd ligand. The solid-state structure has been unequivocally established by X-ray diffraction analysis. Cyclic voltammetric studies on FeCo2(CO)7(bpcd)(μ3-S) reveal the presence of two quasireversible redox responses assigned to the 0/1- and 1-/2- redox couples. The orbital composition of these redox couples has been examined by carrying out extended Hückel MO calculations on the model complex FeCo2(CO)7(H4-bpcd)(μ3-S), with the results being compared to related cluster compounds.

Small organic ‘collector’ ligands play an important role in the recovery of platinum group minerals (PGMs) from the industrial platinum mining process via the froth flotation process, which separates finely ground minerals on the basis of relative hydrophobicity. Design of novel ligands to improve PGM recovery is an ongoing industrial interest. This thesis involves the application of computational chemistry techniques to gain a first-principles understanding of simple mineral-collector ligand interactions, with a view to applying this understanding to the design of novel collector ligands. Experimental techniques are also used, where appropriate, to validate computational modelling in order to gauge the applicability of computational chemistry to this field. Sperrylite (PtAs2), the world’s most common PGM, was used as a model for a typical platinum group sulfide mineral. Pentlandite ((Fe,Ni)9S8) and pyrite (FeS2), two base metal sulfide minerals commonly associated with PGMs, were used as competitor surfaces to gauge collector selectivity. α-quartz (SiO2) was used as to model silicaceous waste material, and pure platinum (Pt) as an internal standard to gauge Pt-collector interactions. Chapter 1 provides an overview of PGM mining with particular focus on the froth flotation process. A brief overview of the computational methods applied in this work is provided in Chapter 2. Chapter 3 presents modelling work based on assessing the various mineral and metal surfaces upon which ligands adsorption is modelled. Stable ‘working surfaces’ are defined by calculating surface energies for various low Miller index cleavages of the bulk unit cells of these solids. Surface stability with respect to slab depth is also assessed. A number of methods, including application of the virtual crystal approximation, a pairwise cluster expansion and explicit site modelling, are used to resolve the issue of positional disorder of the metal sites in pentlandite. This leads to the observation that pentlandite slabs with a higher concentration of Ni atoms at the mineral/vacuum interface are more stable. A global minimum energy bulk unit cell of pentlandite is described. Chapters 4 and 5 deal with the adsorption of collector and aqua ligands onto these surfaces, with Chapter 5 also reporting attempts at rational in-silico ligand design. A novel method for calculating the binding energy of anionic species in periodic systems via a work-function based correction is described and tested for both mono- and dianionic species. Modelling of ethyl xanthate (H5C2OCS2-) and xanthate-based analogues (H5C2XCS2-, where X=N, NH, NC2H5, S, CH, CH2) shows a trend of increased binding strength upon formation of dianionic species. Whilst this observation was supported (to a lesser degree) by geometrical parameters, the extension of the work-function based correction to deal with dianionic species tended to significantly overbind these ligands and so the work function correction was found to be inappropriate for use in models with a charge state greater than -1. Modelling of heterocyclic ligands on selected surfaces shows weaker adsorption than non-heterocyclic species due to unfavourable electronic effects of the delocalised heterocycle on the R-CS2- head group. Efforts in ligand design focussed on optimising the electronic properties of the tail group in the xanthate structure to provide maximum electron density to the CS2- system. The output from this process was p-methoxyphenyl dithiocarbamate (H2CO-C6H4-N=CS2²-), which performed well in computational models. Synthesis of this ligand, as well as protonated Nethyl dithiocarbamate (H5C2NHCS2-) failed, however, due to the intrinsic instability of monosubstituted dithiocarbamates. Attempts to validate modelling results using two experimental techniques are reported in Chapter 6. Firstly, cyclic voltammetry experiments using sperrylite, pentlandite and platinum working electrodes suspended in collector solutions of concentration 1x10-3 M are reported, which show some correlation between the order of calculated binding energies and the relative position of the oxidation potential for the formation of disulfide oxidation products, a process which is affected by surface adsorption. Correlation is best for ethyl xanthate and diisobutyl dithiophospinate, but poor for N,N-diethyl dithiocarbamate ((H5C2)2NCS2-). Secondly, microflotation experiments for the recovery of sperrylite, pentlandite and pyrite using various collector ligands were conducted. Results broadly agree with prior microflotation literature, but show no simple correlation between ligand binding energies and flotation recovery, suggesting that more complex factors than simple ligand/mineral adsorption are involved.

In a phage binding assay, phage clone (3p5A190) expressing a surrogate mas ligand displayed punctate binding and were internalized in cell expressing native mas and GFP-tagged variants. However, the number of bound and internalized phages in cells expressing mas-GFP was substantially less than the cells expressing mas-(Gly10Ser5)GFP and native mas. In parallel, biotinylation experiment quantitatively showed that the extent of mas-(Gly10Ser 5)-GFP translocation was higher than that of mas-GFP. Consistently, cells expressing mas-(Gly10Ser5)-GFP and native mas showed a rapid and sustained increase of intracellular calcium levels upon MBP7 stimulation. By contrast, cells expressing mas-GFP only response to higher concentration of MBP7 challenge and showed a delayed increase of intracellular calcium level. Moreover, cells expressing native mas had a higher proportion (80%) of cells responsive to MBP7 stimulation; in contrast to only 10∼20% of cells expressing mas fusion proteins. / MBP7-like motif was identified in human facilitative GLUT1 and GLUT7 indicating that mas might interact with glucose transporter (GLUT) and regulate cellular glucose uptake. GLUT4 was found to be expressed endogenously in the CHO cell by RT-PCR, but expression of insulin receptor was not detectable. Although no statistical difference was detected in basal glucose uptake among control cells Vc0M80 and cells with different levels of mas expression, cells expressing mas-(Gly10Ser5)-GFP showed a high glucose uptake in response to insulin. Furthermore, basal 2-DOG uptake in Mc0M80 cells was not affected by pretreatment with various kinase inhibitors or transient expression of Rho variants. By contrast, MBP7 was found to induce a significant elevation of glucose uptake specifically in Mc0M80 cells transiently transfected with GLUT1. / Orphan G protein-coupled receptor (GPCR) mas was initially isolated from a human epidermal carcinoma. Previous study from our lab identified a surrogate ligand---MBP7 (mas binding peptide 7) for mas, and suggested that GFP tagging might affect the receptor activity of mas. In this project, three stable CHO cell lines expressing native mas, mas-GFP and mas-(Gly10Ser 5)-GFP were used to characterize receptor activity of mas. / To summarize, direct GFP tagging at the C-terminus of mas decreased its interactions with ligand and downstream signaling molecules. Partial recovery of mas receptor activity by adding a peptide linker was confirmed by phage binding, membrane fusion protein translocation and calcium response. In addition, mas was possibily coupled with GLUT1 to affect cellular glucose uptake via signaling pathways yet to be fully characterized. / Sun, Jingxin. / Adviser: Cheung Wing Tai. / Source: Dissertation Abstracts International, Volume: 71-01, Section: B, page: 0104. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 150-170). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese.

A kinetic study of the reactions of Group VI-B hexacarbonyls with primary amine and halide ligands was undertaken in order to determine the possible mechanisms of these reactions. As well as the expected dissociative pathway, the reactions with the primary amines were seen to proceed by a concurrent pathway which was dependent upon the ligand concentration. Since nitrogen donor ligands are expected to be poor donor ligands, the mechanism proposed was a "dissociative interchange" mechanism which should not be too dependent upon the nucleophilicity of the ligand. Comparison of the rate constants for the amines studied as well as those of the previously investigated Lewis base ligands indicated all such reactions may proceed through the same mechanism. The similarity in rate constants for the ligand-independent and ligand-dependent pathways supports this mechanism. The rate of formation of the final product was seen to be dependent upon the square of the mercuric halide concentration. Therefore, the conversion of Fe(CO)4(HgX)2 to the final product was proposed to proceed by the successive abstraction by each HgX group of two molecules of mercuric halide. These oxidative elimination reactions are related to a chemical model for the intermediate step in the reduction of dinitrogen to ammonia and their similarities and differences are discussed.