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Multi-scale quantum models for RNA catalysis
Multiscale Quantum Models for RNA Catalysis
The York group’s research is focused on the development and application of multi-scale modeling techniques to study the detailed mechanisms of RNA catalysis. The objective of this research is to bring to bear state-of-the-art theoretical methods to the study of the mechanisms of ribozyme catalysis and the factors that regulate reactivity. An overarching theme is to bridge the gap between theory and experiment and progress toward a consensus view of mechanism that may, ultimately, contribute to a deeper understanding of more complex cellular catalytic RNA systems such as the ribosome and spliceosome. Projects include: the study of the L1 ligase riboswitch; the series of prototype RNA enzymes including the hammerhead, hairpin and HDV ribozymes; non-enzymatic models in solution; and the protein analog RNase A. The calculations involve long-time molecular dynamics (MD) simulations of large-scale conformational events, free energy simulations of metal ion binding and pKa shifts in ribozyme active sites, combined quantum mechanical/molecular mechanical simulations of chemical mechanisms of catalysis, and high-level electronic structure calculations of model systems. These calculations are used together to provide deeper insight into mechanisms and aid in the interpretation of experiments. The applications are all computationally intensive, and have varying needs from MD simulations that require a large number of compute cores with fast Infiniband interconnect, to large-scale quantum calculations that have very large memory and disk-intensive requirements. Considerable ongoing effort has been devoted to benchmark and optimize the performance of these codes on MSI’s core systems, including the new Koronis system that was funded by the PI’s NIH high-end instrumentation grant.