Title: Understanding the Mechanisms of RNA catalysis
Speaker: Evelyn Mayaan, Zymeworks Inc.
Abstract RNAs ability to function as a biological catalyst (i.e. a ribozyme) is showing great promise for biomedical technology and drug research to create gene expression inhibitors that target viral and genetic diseases. Due to ribozymes high negative charge and conformational flexibility, metal ions play a key role in stabilizing active RNA conformations and sometimes a catalytic role in the reaction mechanism itself. The focus of this work is on developing a better understanding of the conformational and divalent metal ion requirements that are necessary in RNA catalysis. Early stages of the project involved a systematic Density Functional Theory (DFT) study of Mg(II) ion binding to phosphates and phosphoranes and other biological ligands. These results were used in the development of and extension of the CHARMM27 force field parameters specific to the study of reactive intermediates and divalent metal ion binding in RNA enzymes. With this new force field, several molecular dynamics simulations were carried out on the hammerhead ribozyme system to understand more about the conformational changes, metal ion roles and thio effects of importance to RNA catalysis. Finally, a discussion of metal binding to DNA and its importance to stabilizing phosphate-phosphate repulsions is given.