Development and Application of New Tools for Computational Biophysical Chemistry

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Computer simulations have become an integral part of many areas of chemistry where intermolecular interactions result in complex physical properties that are difficult to interpret without an atomic-scale understanding. This is especially true in biological systems, as computer simulations of the dynamics of proteins are now a routine part of research. The objective of our research group is to develop new simulation methods that will make it possible to simulate biochemically important systems that cannot be studied with existing tools. Our research at Memorial University will use the state-of-the-art Atlantic Computational Excellence Network (ACEnet) supercomputers to address two of these vital but technically challenging subjects: (1) Irreversible enzyme inhibition is a mechanism by which a drug molecule can stop the function of an enzyme by undergoing a chemical reaction with an amino acid in its active site. Existing drugs such as penicillin and aspirin act through irreversible inhibition and there been extensive pharmaceutical research of irreversible inhibitors that target enzymes relating to cancer. Existing computer programs cannot model these enzyme-drug chemical reactions, so we will use hybrid quantum mechanical/molecular mechanical methods to understand and predict the activity of these putative anti-cancer drugs. (2) RNA is a biological macromolecule that is used to transfer genetic information from DNA to ribosomes, where they provide the instructions for protein synthesis. Over the past 15 years, exciting new RNA structures known as riboswitches have been identified. These RNA strands fold into intricate structures that control gene expression when they are bound to molecules they sense. Exploring the structures and dynamics of these rearrangements computationally would be extremely valuable, however these structures are difficult to simulate as they form strong electrostatic interactions with Mg(II) ions in the cell and their binding-induced rearrangements are a complex, involving thousands of atoms. Our research will employ polarizable force fields in conjunction with sophisticated path-finding methods to simulate these processes.