Computational Chemistry

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.

A brief description of two research areas of primary interest is given below.

Biological Chemistry of NO
Nitric oxide (NO) is a simple diatomic radical more commonly associated with atmospheric chemistry and pollution. However, it is now realised that NO is an important biological messenger, playing a central role in the regulation of a number of diverse physiological processes. These processes include, for example, brain development, embryo formation, muscle relaxation and platelet aggregation. Ongoing experimental research into our metabolic pathways is continually revealing new roles for NO. S-nitrosothiols, chemical species containing an -SNO group, are thought to be the way which NO is transported around the body, or stored for later use. Consequently, they are also of interest as potential therapeutic drugs. However, they are often highly unstable and hence, difficult to study experimentally. Furthermore, how S-nitrosothiols may interact with other biologically important species is also unclear. Our computational studies focus on the properties and chemistry of S-nitrosothiols, and their interactions with other biological species such as enzymes.
Ribozymes
Ribozymes are catalytic RNA molecules, i.e., they are enzymes whose catalytic function is performed by ribonucleic acids. This differs from the traditional view that all enzymes were catalytic proteins. Ribozymes have been found to catalyse some of the same reactions as protein enzymes. Indeed, it has been postulated that in the initial stages of life on earth, RNA molecules carried the genetic information and catalysed the necessary reactions. However, proteins may be built from at least 20 different amino acids, each having its own unique functional group. In contrast, ribozymes are built from just 4 nucleobases, all of which possess quite similar functionality, e.g., hydrogen bonding groups. Thus, they offer a new approach to biological catalysis, and catalysis in general. However, how ribozymes may employ nucleic acids to catalyse biological reactions is still unclear. Thus it is important to better understand how ribozymes perform their various catalytic functions. Present studies in our group use computational methods to investigate various ribozyme catalysed reactions, and the properties of nucleic acids.

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