"The underlying physical laws necessary for the mathematical theory of a large part of physics and the whole of chemistry are thus completely known, and the difficulty is only that the exact application of these laws leads to equations much too complicated to be soluble."

P. A. M. Dirac, 1929


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Research Intersts:
Central to understanding the chemistry of cells is elucidating the chemistry of important biomolecules and their interactions. A class of biomolecules of particular interest is enzymes; molecules that catalyse the broad range of reactions essential for life. In addition to the fundamental knowledge to be learned, this interest is due in part to the medical and industrial benefits to be obtained. For example, the aim of therapeutic drugs is often to enhance or inhibit the function of a specific enzyme. Computational chemistry uses computers to model the chemistry and reactions of chemical systems. Such approaches are used, for example, to study problems that may be too difficult to study experimentally or to provide insight into observed phenomena. Our research group uses the methods of computational and theoretical chemistry to investigate the chemistry and reactions of various biomolecules, in particular biochemical catalysts. Brief overviews of some various areas studied by our group are described below.

The chemistry of cofactors:
Many enzymes require essential cofactors in order to perform their catalytic function. Such species often act as a source of functional groups or electrons. Their behaviour can differ between enzymes due to chemical variations in their binding sites which influence the structure and properties of the cofactor, tuning it to its role in the given enzyme. However, how such differences in the binding site affect the cofactors are often unknown. Modeling cofactor binding can thus provide greater insight into their roles in enzymes.


Modeling active sites:
Enzymes exploit cooperative effects of chemical interactions and environmental effects in order to catalyse reactions. In addition to investigating the actual catalytic mechanism, by modeling the structure of the active site one can study the role of individual enzyme-substrate interactions in the mechanism. Such studies not only provide deeper insight into how an enzyme actually functions, but also into, for example, what may be the consequences of a particular mutation. A focus of our research is the mechanisms and properties of ribo- and DNAzymes (catalytic nucleic acids) and novel protein metalloenzymes.

DNA multiplexes:
During replication, single stranded DNA at the end of chromosomes are progressively shortened, thus regulating cell division. In cancer cells, however, certain enzymes are capable of repairing these ends, leading to immortality. It is thought that these single strands of DNA can form intra- or inter-strand complexes, leading to the formation of variously stacked multiplexes, thus making themselves unavailable to repair enzymes. As a result, there is considerable interest in developing therapeutic drugs that specifically bind such complexes. Hence, better understanding of the structure and properties of such multiplexes could lead to the development of new therapies.

Transition Metals-Iron:

Iron is the most important Transition Metal (TM) for life vital to both plants and animals. Iron containing proteins have several key roles. In particular these roles are:

1) Enzymatic catalysis

2) Ligand transport

3) Electron transfer

4) Light-harvesting



Interestingly 75% of iron in the human body is contained in heme and as a result is essential for human life. Two key aspects of heme chemistry are the biochemistry and synthesis of the molecule. The synthesis of heme occurs via a complex pathway involving eight key steps. The fifth step is catalysed by the enzyme Uroporphyrinogen Decarboxylase III. An enzyme that requires no cofactor in the catalytic decarboxylation. In addition this enzyme is found to use two active site arginine residues to catalyse the decarboxylation of the substrate. Such a finding is counterintuitive to the amino acid's typical biochemical nature of being strictly a basic amino acid residue.

Alternatively, Fe-containing proteins/enzymes can also be classified as being non-heme. Such enzymes contain an Fe center ligated by only amino acid residues. In heme, the coordination of the Fe center is very rigid; there is little flexibility in the aromatic macrocycle (PPIX)). However, when the Fe is only ligated by amino acid residues a greater flexibility of the coordination geometry exists. This difference of flexibility has been shown to significantly affect the chemical reactivity of the transition metal ion.

While quite a bit of information has been gleaned about the chemical behaviour and reactivity of iron there still remains several questions into its role in biochemistry.



Carbohydrates are the most abundant biomolecule on earth. More importantly, however, they play diverse functions in nature and have an increasing array of roles in industrial and medicinal applications. For example, in nature they are found as key components in nucleic acids, cell walls (e.g., cellulose), exoskeletons (e.g., chitin), metabolites (e.g., NAD+), energy molecules (e.g., ATP), energy storage (e.g., starch and glycogen), skeletal joint lubricants, and blood sugar type expression while simultaneously they are increasingly finding use as components of therapeutic drugs. Unfortunately, the role of the sugar and its biochemistry are often not well understood. For example, the glycosidic bond, the typical bond that holds monosaccharides together or that attaches a nucleobase to a sugar in nucleosides is one of the 'strongest' bonds found in biochemistry. For instance, the half-life of amide bonds in a peptide under standard conditions has been estimated at 125 years. In contrast, the half-life of the glycosidic bonds in cellulose under the same conditions is approximately 5 million years! Fortunately, within organisms, a class of enzymes known as glycoside hydrolases are able catalyse the hydrolysis of such bonds at tremendous rates and in fact, are amongst some of the most effective enzymes known. However, while some utilise a more typical acid/base type mechanism, some are known to use a redox mechanism in which a hydroxyl group remote from the glycosidic bond is first oxidized. Our current research in this area involves the use of a broad array of computational methods ranging from MD to DFT and large active site chemical models to QM/MM and very large enzyme models to study, for example, glycosidic bond cleavage via redox mechanisms.

Sulfur Biochemistry:

The importance of sulfur in biochemical systems has long been recognised, particularly since the discovery of insulin in the early half of the 20th-century and the key role of sulfur's in its structure and hence, function. Of the '20 amino acids' two contain sulfur; cysteine and methionine. However, it is also found in various other forms and biomolecules such as, for example, sulfonates (e.g., carbohydrate chemistry: heparin and heparan sulfate – key biomolecules in wound healing) and iron-sulfur clusters. Consequently, sulphur containing enzymes and molecules have been found to play central roles in diverse biochemical processes such as nucleophilic and redox mechanisms and metabolism of toxins including 'free-radicals' and reactive oxygen species (ROS's). In addition, sulfur containing bioactive molecules are also finding increasing use as, for instance, therapeutic drugs. These diverse roles of sulfur are due in part to its relationship to oxygen and its ability to form hypervalent compounds.

For example, we have recently used DFT-based methods in combination with large-chemical models to investigate the catalytic mechanism of the ubiquitous group of enzymes known as methionine sulfoxide reductases (Msr's); important enzymes in ROS defense mechanisms. Methionine is thought to sometimes play the role of 'sacrificial lamb' in oxidative damage of proteins. This is because it is one of the most readily oxidized amino acids, yet the resulting oxidized products (e.g., methionine sulfoxide: Met-SO) can be reversibly reduced by Msr's to regenerate the original methionine residue. Furthermore, this can be done without damaging the protein. Remarkably, the preferred pathway was shown to proceed via a sulfonium intermediate, (R1S—SR2R3)+, with an alternate less-preferred pathway being found to also involve a sulfenic acid (RSOH).

Computational investigations on the catalytic mechanisms of such enzymes, and the underlying fundamental chemistry that drives them, will lead to get a deeper understanding of sulfur's functionality in biochemistry.



Deamination, and naturally by extension the reverse reaction - amination, is an important fundamental reaction that often plays a key role in many physiological processes. For example, nucleobase deamination is one of the major pathways of DNA damage. In addition, it also one of the key processes of metabolic regulation of amino acid levels.

There are several possible mechanistic routes by which deamination may occur, the major path being via hydrolysis. However, it may also occur via, for example, redox chemistry. One bacterial enzyme that uses such an approach is P. pneumoniae ornithine cyclodeaminase. Furthermore, it is believed to use a mechanism similar to that of related enzymes involved in regulation of amino acid levels and ion concentrations within the mammalian eye and whose malfunctioning has been implicated in the formation of cataracts. More specifically, it uses the redox cofactor NAD+ and catalyses the stereospecific cyclization of the amino acid ornithine to give L-proline and ammonia. Thus, a greater understanding of its catalytic pathway can provide invaluable insights into that may lead to the development of therapeutic drugs for treatment of various mammalian eye conditions.



Aboelnga, M.; Hayward, J. J.; Gauld J. W.* (2017) Unraveling the Critical Role Played by Ado762'OH in the Post-Transfer Editing by Archaeal Threonyl-tRNA Synthetase   J. Phys. Chem. B. Article ASAP

Aboelnga, M.; Hayward, J. J.; Gauld J. W.* (2017) A Water-Mediated and Substrate-Assisted Aminoacylation Mechanism in The Discriminating Aminoacyl-tRNA Synthetase GlnRS and Non-Discriminating GluRS   Phys. Chem. Chem. Phys. 19, 25598-25609

Aboelnga, M.; Hayward, J. J.; Gauld J. W.* (2017) Enzymatic Post-Transfer Editing Mechanism of E. coli Threonyl-tRNA Synthetase (ThrRS): A Molecular Dynamics (MD) and Quantum Mechanics/Molecular Mechanics (QM/MM) Investigation   ACS. Catal., 7, 5180-5193

Gauld J. W. (2017) Book Review: "Simulating Enzyme Reactivity: Computational Methods in Enzyme Catalysis", I. Tun and V. Moliner (Eds.), The Royal Society of Chemistry Publishing, UK, 2017.   Computational and Theoretical Chemistry, 1112, 67-68

Dokainish, H.; Simard, D.; Gauld J. W.* (2017) A Pseudo-Hypervalent Sulfur Intermediate As An Oxidative Protective Mechanism In The Archaea Peroxiredoxin Enzyme ApTPx   J. Phys. Chem. B. 121, 6570-6579

Aboelnga, M.; Gauld J. W.* (2017) The Roles of the Active Site Zn(II) and Residues in Substrate Discrimination by Threonyl-tRNA Synthetase: An MD and QM/MM Investigation   J. Phys. Chem. B., 121, 6163-6174

Wei, W.; Gauld J. W.*; Monard, G.* (2017) Computational Insights Into Substrate Binding and Catalytic Mechanism of the Glutaminase Domain of Glucosamine-6-Phosphate Synthase (GlmS)   RSC Advances, 7, 29626-29638

Wei, W.; Gauld J. W.*; Monard, G.* (2017) Pretransfer Editing in Threonyl-tRNA Synthetase: Roles of Differential Solvent Accessibility and Intermediate Stabilization   ACS Catal. 7, 3102-3112

Ion, B. F.; Aboelnga, M. M. and Gauld, J. W. * (2016) Insights From Molecular Dynamics on Substrate Binding and Effects of Active Site Mutations in Δ1-Pyrroline-5-Carboxylate Dehydrogenase.   Can J. Chem. 94,1151. (Invited/Journal Cover/2017 CJC Best Paper Award)

Jarosz, A. P., Wei, W., Gauld, J. W., Auld, J., zcan, F.,Aslan, M., Mutus, B.* (2015) Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is inactivated by S-sulfuration in vitro.   Free Radic. Biol. Med, 89, 512

Fortowsky, G.; Simard, D.; Aboelnga, M. and Gauld, J.W. * (2015) Substrate-Assisted and Enzymatic Pretransfer Editing of Nonstandard Amino Acids by Methionyl-tRNA Synthetase   Biochemistry, 54, 5757

Dokainish, H.; Gauld, J.W.* (2015) Formation of a Stable Iminol Intermediate in the Redox Regulation Mechanism of Protein Tyrosine Phosphatase 1B (PTP1B) ACS Catalysis, 5, 2195-2202.Invited.

Bogdan F. Ion.; Erum Kazim; Gauld, J.W.* (2014) A Multi-Scale Computational Study on the Mechanism of Streptococcus pneumoniae Nicotinamidase (SpNic)   Molecules, 19, 15735-15753. Invited / Journal Cover.

Aboelnga, M.; Awad M.; Gauld, J.W.; Moustafa M.(2014) An assessment to evaluate the validity of different methods for the description of some corrosion inhibitors J Mol. Model., 20, 2422.

Macdonald, C. A.; Bushnell, E.; Gauld, J.W.; Boyd, R.* (2014) The catalytic Mechanism of leukotriene C4: a critical step in inflammatory processes.   Phys. Chem. Chem. Phys.16,16284

Dokainish, H.; Ion, B.F; Gauld, J.W.* (2014) Computational investigations on the catalytic mechanism of maleate isomerase: the role of the active site cysteine residues Phys. Chem. Chem. Phys., 16, 12462-12474.

Gherib, R.; Dokainish, H. M.; Gauld, J.W.* (2014) Multi-Scale Computational Enzymology: Enhancing Our Understanding of Enzymatic Catalysis. Int. J. Mol. Sci.  15, 40-422.

De Luna P.; Bushnell, E.; Gauld J.W.* (2013) A Molecular Dynamics Examination on Mutation-Induced Catalase Activity in Coral Allene Oxide Synthase. J. Phys. Chem. B, 117, 14635.

Bushnell, E.A.C.; Gherib, R.; Gauld, J.W.* (2013) Insights into the Catalytic Mechanism of Coral Allene Oxide Synthase: A Dispersion Corrected Density Functional Theory Study. J. Phys. Chem. B, 117, 6701-6710.

De Luna, P.; Bushnell, E.; Gauld, J.W.* (2013) A Density Functional Theory Investigation into the Binding of the Antioxidants Ergothioneine and Ovothiol to Copper. J. Phys. Chem. A, 117, 4057-4065.

Dokainish, H.; Gauld, J.W.* (2013) An MD and QM/MM study on the Catalytic Reductase Mechanism of Methionine Sulfoxide Reductase A (MsrA): Formation and Reduction of a Sulfenic Acid. Biochemistry 52 (10) 1814-1827.

Bushnell, E.A.C.; Jamil, R.; Gauld, J.W.* (2013) Gaining Insight into the Chemistry of Lipoxygenases (LOXs): A Computational Investigation Into The Catalytic Mechanism of 8R-LOX. J. Biol. Inorg. Chem. 18 (3) 343-355.

Bushnell, E.A.C.; Fortowsky, G.B.; Gauld, J.W.* (2012) Iron-Oxo Species and the Oxidation of Imidazole: Insights into the Mechanism of OvoA and EgtB. Inorg. Chem. 51 (24) 13351–13356.

Huang, W.J.; Gauld, J.W.* (2012) Tautomerization in the UDP-Galactopyranose Mutase Mechanism: A DFT-Cluster and QM/MM Investigation. J. Phys. Chem. B  116 (48) 14040–14050.

Ion, B.F.; Bushnell, E.A.C.; De Luna, P.; Gauld, J.W.* (2012) An MD and QM/MM Study on Ornithine Cyclodeaminase (OCD): A Tale of Two Iminiums. Int. J. Mol. Sci., 13, 12994-13011. Invited.

Bushnell, E.A.C.; Gauld, J. W.* (2012) An Assessment of Standard, Hybrid, Meta and Hybrid-Meta GGA Density Functional Theory Methods for Open-Shell Systems: the Case of the Non-Heme Iron Enzyme 8RLOX. J. Comput. Chem 34 (2) 141-148

Huang, W.J.; Gherib, R.; Gauld, J.W.* (2012) An Active Site Water Broadens Substrate Specificity in S-Ribosylhomocysteinase (LuxS): A Docking, MD, and QM/MM Study. J. Phys. Chem. B, 116, 8916-8929.

Bushnell, E.A.C.; Huang, W.J.; Llano, J.; Gauld, J.W.* (2012) Molecular Dynamics Investigation into Substrate Binding and Identity of the Catalytic Base in the Mechanism of Threonyl-tRNA Synthetase. J. Phys. Chem. B, 116, 4205-5212.

Almasi, J.; Bushnell, E.A.C.; Gauld, J.W.* (2011). A QM/MM-based Computational Investigation on the Catalytic Mechanism of Saccharopine Reductase. Molecules, 16, 8569-8589. Invited.

Huang, W.J.; Bushnell, E.A.C.; Francklyn, C.S.; Gauld, J.W.* (2011). The α-Amino Group of the Threonine Substrate as The General Base During tRNA Aminoacylation: A New Version of Substrate-Assisted Catalysis Predicted by Hybrid DFT, J. Phys. Chem. B, 115, 13050-13060 Invited.

Robinet, J.J.; Dokainish, H.; Paterson, D.J.; Gauld, J.W.* (2011). A Sulfonium Cation Intermediate in the Mechanism of Methionine Sulfoxide Reductase B: A DFT Study, J. Phys. Chem. B, 115, 9202-9212.

Erdtman, E.; Bushnell, E.A.C.; Gauld, J.W.; Eriksson, L.A.* (2011) Computational Studies on Schiff Base Formation: Implications for the Catalytic Mechanism of Porphobilinogen Synthase, Comp. Theor. Chem., 963, 479-489. *highlighted by editors as part of the celebration of the 1000th volume.

Amiralaei, S.; Gauld, J.; Green, J.R.* (2011). Dehydrotropylium-Co2(CO)6 Ion. Generation, Reactivity and Evaluation of Cation Stability. Chem. Eur. J., 17, 4157-4165.

Bushnell, E.A.C.; Erdtman, E.; Llano, J.; Eriksson, L.A.; Gauld, J.W.* (2011). The First Branching Point in Porphyrin Biosynthesis: A Systematic Docking, MD and QM/MM Study of Substrate Binding and Mechanism of Uroporphyrinogen-III Decarboxylase. J. Comput. Chem., 32, 822-834.

Huang, W.J.; Llano, J.; Gauld, J.W.* (2010). A DFT Study on the Catalytic Mechanism of UDP, Can. J. Chem., 88, 804-814. Invited: Special issue in honour of Prof. R. Boyd.

Erdtman, E.; Bushnell, E.A.C.; Gauld, J.W.; Eriksson, L.A.* (2010). Computational Insights into the Mechanism of Porphobilinogen Synthase, J. Phys. Chem. B, 114, 16860-16870.

Huang, W.J.; Llano, J.; Gauld, J.W.* (2010). Redox Mechanisms of Glycosidic-Bond Hydrolysis Catalyzed by 6-Phospho-a-Glucosidase (GlvA): A DFT Study, J. Phys. Chem. B, 114, 11196-11206.

Liu, H.; Llano, J.; Gauld, J.W.* (2009). A DFT Study of Nucleobase Dealkylation by the DNA Repair Enzyme AlkB, J. Phys. Chem. B, 113, 4887-4898.

Liu, H.; Gauld, J.W.* (2009). Protonation of Guanine Quartets and Quartet Stacks: Insights from DFT Studies, Phys. Chem. Chem. Phys., 11, 278-287.

Robinet, J.J.; Cho, K.-B.; Gauld, J.W.* (2008) A Density Functional Theory Investigation on the Mechanism of the Second Half-Reaction of Nitric Oxide Synthase, J. Am. Chem. Soc., 130, 3328-3334.

Robinet, J.J.; Gauld, J.W.* (2008). DFT Investigation on the Mechanism of the Deacetylation Reaction Catalyzed bt LpxC, J. Phys. Chem. B, 112, 3462-3469.

Liu, H.; Gauld, J.W.* (2008). Substrate-Assisted Catalysis in the Aminoacyl Transfer mechanism of Histidyl-tRNA Synthetase: A Density Functional Theory Study, J. Phys. Chem. B, 112, 3462-3469.

Robinet, J.J.; Baciu, C.; Cho, K.-B.; Gauld, J.W.* (2007). A Computational Study on the Interaction of the Nitric Oxide Ions NO+ and NO with Aromatic Amino Acids, J. Phys. Chem. A, 111, 1981-1989.

Liu. H.; Robinet, J.J.; Ananvoranich, S.; Gauld, J.W.* (2007). Density Functional Theory Investigation on the Mechanism of the Hepatitis Delta Virus Ribozyme, J. Phys. Chem. B, 111, 439-445.

Other refereed publications (reviews / chapters / letters)

Ban, F.; Gauld, J.W.; Wetmore, S.D.; Boyd, R.J.* The Calculation of the Hyperfine Coupling Tensors of Biological Radicals. In EPR of Free Radicals in Solids: Trends in Methods and Applications, Lund, A. and Shiotani, M. (Eds.); Springer 2012 (37 pages; In Press).

Bushnell, E.A.C.; Huang, W.J.; Gauld, J.W.* (2012). Applications of Potential Energy Surfaces In The Study of Enzymatic Reactions, Adv. Phys. Chem. 2012 (15 pages; doi:10.1155/2012/867409) Invited: Special issue Accurate Potential Energy Surfaces and Beyond: Chemical Reactivity, Binding, Long-Range Interactions, and Spectroscopy.

Robinet, J.J.; Dokainish, H.; Paterson, D.J.; Gauld, J.W.* (2011). Reply to the "Comment on 'A Sulfonium Cation Intermediate in the Mechanism of Methionine Sulfoxide Reductase B: A DFT Study'", J. Phys. Chem. B, 115, 10776-10777.

Bushnell, E.A.C.; Llano, J.; Eriksson, L.A.; Gauld, J.W.* (2011). Mechanisms of Mutagenic DNA Nucleobase Damages and Their Chemical and Enzymatic Repairs Investigated by Quantum Chemical Methods In Selected Topics in DNA Repair, Clark C. Chen (Ed.), InTech (ISBN: 978-953-307-606-5).Invited.

Llano, J.; Gauld, J.W.* (2010) Mechanistics of Enzyme Catalysis: From Small to Large Active-Site Models In Quantum Biochemistry: Electronic Structure and Biological Activity, Matta, C. (Ed.), Wiley-VCH Verlag GmbH & Co. KGaA, p. 643-666. Invited due to our extensive work in computational enzymology.

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