445 research outputs found
Gauld, J (James), NX36384
No full textThis record was harvested from a previous catalogue system and will be withdrawn in 2025. Information in this record may be superseded or incomplete. Visit this record in UMA's new catalogue at: https://archives.library.unimelb.edu.au/nodes/view/387029Surname: GAULD. Given Name(s) or Initials: J (JAMES). Military Service Number or Last Known Location: NX36384. Missing, Wounded and Prisoner of War Enquiry Card Index Number: 45406.208799
Item: [2016.0049.19322] "Gauld, J (James), NX36384
Python projects / Laura Cassell, Alan Gauld.
No full text"Wrox programmer to programmer"--Cover.computer bookfair2016Includes bibliographical references (pages 327-331) and index.xxx, 350 p. :Provides information on real-world Python programming, including a review of Python data types, using control structures, managing data, creating modules and packages, and debugging code
Computational Investigations on Enzymatic Catalysis and Inhibition
No full textEnzymes are the bimolecular “workhorses” of the cell due to their range of functions and their requirement for cellular success. The atomistic details of how they function can provide key insights into the fundamentals of catalysis and in turn, provide a blueprint for biotechnological advances. A wide range of contemporary computational techniques has been applied with the aim to characterize recently discovered intermediates or to provide insights into enzymatic mechanisms and inhibition. More specifically, an assessment of methods was conducted to evaluate the presence of the growing number 3– and 4–coordinated sulfur intermediates in proteins/enzymes. Furthermore, two mechanisms have been investigated, the μ-OH mechanism of the hydrolysis of dimethylphosphate in Glycerophosphodiesterase (GpdQ) using five different homonuclear metal combinations Zn(II)/Zn(II), Co(II)/Co(II), Mn(II)/Mn(II), Cd(II)/Cd(II) and Ca(II)/Ca(II) as well as a preliminary study into the effectivness of boron as an inhibitor in the serine protease reaction of class A TEM-1 β-lactamases
Birmingham News sleeve BN0065891
No full textAnne Leslie Deery / James Brian Gauld / [Work order included
Computational Insights into the High-Fidelily Catalysis of Aminoacyl-tRNA Synthetases
No full textObtaining insights into the catalytic function of enzymes is an important area of research due to their widespread applications in the biotechnology and pharmaceutical industries. Among these enzymes, the aminoacyl-tRNA synthetases (aaRSs) are known for their remarkable fidelity in catalyzing the aminoacylation reactions of tRNA in protein biosynthesis. Despite the exceptional execution of this critical function, mechanistic details of the reactions catalyzed by aminoacyl-tRNA synthetases remain elusive demonstrating the obvious need to explore their remarkable chemistry. During the PhD studies reported in this thesis the mechanism of aminoacylation, pre-transfer editing and post-transfer editing catalyzed by different aaRS have been established using multi-scale computational enzymology. In the first two chapters a detailed information about aaRS and the addressed questions was given in addition to an overview of the used computational methodology currently used to investigate the enzymatic mechanisms. The aminoacylation mechanism of threonine by Threonyl-tRNA synthetases, glutamine by Glutaminyl-tRNA synthetases and glutamate by Glutamyl-tRNA synthetases have been clearly unveiled in chapter 3 and 4. Also, valuable information regarding the role of cofactors and active site residues has been obtained. While investigating the post-transfer editing mechanisms, which proceed in a remote and distinct active site, two different scenarios were experimentally suggested for two types of threonyltRNA synthetase species to correct the misacylation of the structurally related serine. We explored these two mechanisms as in chapters 5 and 6. Moreover, the synthetic site in which the aminoacylation reaction is catalyzed, is also responsible for a second type of proofreading reaction called pre-transfer editing mechanism. In chapter 7, this latter mechanism has been elucidated for both Seryl-tRNA synthetases and Isoleucyl-tRNA synthetases against their non-cognate substrates cysteine and valine, respectively. In chapter 8, an assessment QM/MM study using a variety of DFT functionals to represent the chemically active layer in aminoacylation mechanism of the unnatural amino acid ß-Hydroxynorvaline as catalyzed by Threonyl-tRNA synthetase has been carried out. Overall, it was found that substrateassisted mechanisms are a common pathway for these enzymes. One important application of such information is to establish the criteria required for any candidate to inhibit the catalytic functions of aaRS, which was applied in chapter 9 to screen potential competitive inhibitors able to efficiently block the bacterial Threonyl-tRNA synthetases. The investigations reported herein should provide atomistic details into the fundamental catalytic mechanisms of the ubiquitous and ancient aaRS enzymes. Consequently, they will also help enable a much-needed deeper understanding of the underlying chemical principles of catalysis in general
Computational Studies of Multi-Active Site Enzymes
No full textMulti-scale computational approaches have been applied to investigate the catalytic mechanisms of (i) yeast mitochondrial threonyl-tRNA synthetase (MST1) pre-transfer editing and, (ii) glutamine deamination by glucosamine-6-phosphate synthase (GlmS). MST1: MD and QM/MM-MD methods were used to examine (i) differences in the binding of its cognate and non-cognate Thr- and Ser-AMP substrates respectively, and (ii) mechanism of hydrolytic pre-transfer editing. In contrast to bound Thr-AMP, bound Ser-AMP is less constrained; i.e., greater positional variability, and as a result more waters are able to permeate the active site. Mechanistically, Thr-AMP hydrolysis occurs in two steps via a tetrahedral oxyanion intermediate. For Ser-AMP, however, formation of the oxyanion proceeds via a metastable intermediate while the second step, cleavage of the Ccarb-OP bond, occurs as for Thr-AMP with similar energy barriers. Umbrella sampling shows that mechanism differences are due to a greater number of active site waters stabilizing the forming oxyanion in Ser-AMP, compared to Thr-AMP. As a result, the relative free energies of the rate-limiting barriers as well as that of the hydrolyzed products for Thr-AMP (14-19 and 4-10 kcal mol-1, respectively) are markedly higher than for Ser-AMP (7-12 and 0-5 kcal mol-1, respectively). That is, MST1 thermodynamically and kinetically preferentially edits against non-cognate substrate Ser-AMP, in agreement with experiment. GlmS: MD and QM/MM studies were performed to examine the (i) protonation state of the mechanistically important amine of its N-terminal cysteinyl (Cys1) and its effect on its glutaminase domain and, (ii) mechanism by which it deaminates its glutamine substrate. Proton affinity studies suggest that at physiological pH, the Cys1-NH2 group prefers to be neutral, and that if protonated, the active site is structurally less consistent. When the Cys1-NH2 group acts as the required mechanistic base the rate limiting step corresponds to nucleophilic attack of a water on the covalently cross-linked thioester intermediate with a free energy barrier of 78.2 kJ mol-1
Computational Insights into Nitrogen-Related Biocatalysis
No full textNitrogen-dependent reactions are prevalent and essential in many biochemical systems. These chemical reactions are ensured to occur at physiological rates via the catalytic power of enzymes. Important to some reactions, their catalysis is also dependent on cofactors such as NAD+, metal ions, and active site water molecules. In this dissertation, several nitrogen-related biochemical systems are investigated using complementary computational methods such as docking, molecular dynamics simulations, quantum chemical clusters, and quantum mechanics/molecular mechanics. The use of this multi-scale computational approach has been successfully applied to investigate the catalytic mechanisms, substrate binding, and roles of key active site residues of both metallo- (e.g., Streptococcus pneumoniae Nicotinamidase) and non-metalloenzymes (e.g., Ornithine Cyclodeaminase). Additionally, in silico mutations were done to examine the impact genetic mutations have on the catalytic site of physiologically important enzymes (e.g., ∆1-pyrroline-5-carboxylate dehydrogenase). The specificity of enzymes involved in protein synthesis (e.g., L-lysyl-tRNA synthetase) has also been studied along with their ability to discriminate with high-fidelity between chemically and structurally similar ligands. The application of quantum chemical cluster methods to explore multiple X-ray crystal structures of an enzyme (e.g., pseudouridine-5'-monophosphate glycosidase) provided a greater understanding of its reaction mechanism. Moreover, the importance in carefully selecting a starting point from available crystal structures was shown when applying molecular modeling and simulation methods
Computational Investigations into Nucleic Acid-Related Chemistry
No full textNucleic acids are biopolymers of nucleotides, which are composed of a phosphate, nucleobase and ribose sugar. In addition to acting as the genetic carrier, nucleic acids play a variety of other important roles in biological systems. In this thesis, nucleic acid-related chemistry is investigated using computational methods. Chapter 1 presents an overview of the problems addressed in this thesis, whereas Chapter 2 discusses various theoretical methods. Then, Chapter 3 investigates the feasibility of using the phosphate oxygens as the general base to catalyze the aminoacyl transfer reaction in histidyl-tRNA synthetase. Three possible mechanisms with different phosphate oxygens acting as the base to abstract the 3'-OH group of A76 were examined and compared. Chapter 4 elucidates the catalytic mechanism of the repair of an alkylated nucleobase by the enzyme AlkB. It was found that this mechanism consists of four stages and that our calculated barrier for the rate-controlling step is in good agreement with experimental studies. Chapter 5 addresses the catalytic mechanism of the HDV ribozyme. Both cytosine and hydrated Mg2+ ion were found to be involved in the reaction with the former acting as the acid and the latter as the base. Chapter 6 studies the protonation of guanine quartets and quartet stacks. Each quartet plane was found to be able to accept maximally two protons. Chapter 7 deals with the interactions of metal ions with ribose and locked ribose. Four metal ions, Na+, K+, Mg2+ and Cd2+ were chosen and their properties upon interacting with ribose and locked ribose were compared. Chapter 8 presents the influences of the selection of computational methods and chemical models on the amide bond formation as catalyzed by the ribosome. Two proton transfer processes involving four- and six-membered transition structures were systematically examined using a variety of methods. Finally, Chapter 9 summarizes the main conclusions and possible extensions of the current work
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