Using side-chain vibrational interactions as a computational model for protein allostery

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Media reports covering the success of the Human Genome Project have stressed the importance of DNA molecules, but there has been relatively little reporting about the many research efforts dealing with proteins. While DNA is essential for the storage and transmission of genetic information, the significant life processes of a living cell are primarily accomplished by the thousands of different protein molecules that provide structural form, movement capabilities, acceleration of chemical reactions, and signal transmission (for example, hormones and membrane proteins in neural synapses). Proteins can change shape and are often described as molecular motors that can interact or bind with other proteins and various smaller molecules called ligands (for example, drugs). An important phenomenon that is often associated with ligand binding is called allostery: ligand binding initiates an internal fluctuation or some type of information transfer within the protein culminating in a structural change elsewhere in the protein, and this change allows it to interact with a different molecule. The exact mechanism underlying allostery is not yet fully understood even though several ideas have been set forth in the research community.****Our research project will undertake the computational modeling of allostery by treating the interior of a protein as a set of entities that interact using vibrational couplings. The computational analysis will determine the strength of various couplings to predict the existence of internal pathways that would explain the allosteric behaviour. When this goal has been achieved the next step is to evaluate the success of the predictions by investigating how well these pathways can explain the behaviour of previously studied proteins that are known to be allosteric. The final goal of the project would be to establish how allostery is compromised or eliminated when the protein is modified, as might happen in disease states such as cancer.****The research value of the final goal is to understand how protein allosteric dysfunctionality may arise from amino acid mutations. In general, a more comprehensive understanding of allostery would have many practical benefits for drug design, in particular, drugs that work by imparting allosteric modulation. These insights and algorithmic strategies will have significant value for the Canadian pharmaceutical industry, which is in constant need of innovative techniques to handle new biological targets.******