Electronic Structure Theory: Algorithms, Applications and Cheminformatics

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Introduction: No computational methodologies currently exist that can deal reliably with macromolecules or complex chemical process. Rational drug-design, rational design of new materials, catalysis, reactions in solution, excited states of large molecules, surface chemistry, and protein folding are all examples of problems that are very challenging to computational chemists. The research focuses broadly on the development of novel and innovative methods for preforming electronic structure calculations. The long-term goal is to develop reliable methodologies for dealing with very large molecules, such as proteins. The theories should also be simple enough to provide insight into the chemistry. Electronic Structure Theory: The molecular density and the molecular radial density (defined by my group) along with their gradient and Laplacian, will be used to study the properties of both Atoms and Bonds In Molecules (ABIM). With ABIM it is possible to compute a number of properties associated with a given atom or bond in a molecule. Such studies will provide new insight into chemical bonding and structure-reactivity by studying the change in chemical bonds during a chemical reaction. Molecular descriptors will also be developed using the ABIM properties. These will provide a novel and valuable set of similarity measures for use in areas such as drug design. A database of Atoms-In-Molecules (AIM) densities and radial densities will be created and methods will be developed to use these AIM to generate the density, or radial density, of macromolecules. Given these densities, we will develop algorithms to perform conformational energy searches using the density of the entire macromolecule. A QM/AIM approach, in which the molecule is divided into a region described by AIM derived densities and a smaller region (e.g., the active site) is solved using wavefunction or density functional theory. Such an approach may also be useful in modelling solvation. An electronic structure theory in which, instead of partitioning the electronic density into atomic contributions, the molecular density will be built from atomic densities using a variational approach. Models which can reliably predict the correlation energy will be developed based on properties that can be easily calculated. These models will help us develop composite methods that are fast and applicable to much larger systems then with the current methods. Investigating Reaction Mechanisms: We will continue investigating reaction mechanisms, especially deamination and deamidation reactions. These include the deamination of cytosine, adenine, guanine and the deamidation of glutamine. The role of solvent and catalysts will be investigated. In our studies we will apply the methodologies described above to provide insight into these reactions. These reactions are important in mutagenesis, carcinogenesis and hyperammonemia (glutamine).