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RNA Structure, Folding, and Catalysis

It has become increasingly apparent that the role of RNA in cellular function is vast, ranging from the regulation of gene expression and signaling pathways to catalysis of important biochemical reactions, including protein synthesis and pre-mRNA splicing. An overarching goal of our lab is to bring to bear state-of-the-art theoretical methods to the study of RNA function. This function is critically tied to the structure and dynamics of RNA, its catalytic properties, and how these properties are influenced by its aqueous solvation environment, and in particular, the specific ionic atmosphere.

Our research focus in RNA structure, folding and catalysis include:

  • RNA Structure and Dynamics
  • Mechanisms of Ribozyme Catalysis
  • RNA Electrostatics and Ion Atmosphere

RNA Structure and Dynamics
RNA provides a wide range of functions in cells, all of which are tied, at the molecular level, to structure an dynamics. We study RNA structure and dynamics using molecular simulations that provide a dynamical view of the conformational landscape. RNA presents special challenges for molecular simulations, owing to its high degree of charge and conformational variation that require careful consideration of electrostatic interactions, and specialized techniques for sampling. We push the cutting edge in the development of these methods, as well as new force fields for more accurate and robust modeling of RNA. These methods allow us to characterize the structure and dynamics of RNA in solution, which, together with experiments, provide deep insight into its molecular function.

Mechanisms of Ribozyme Catalysis
The novel catalytic properties of RNA have been an area of intense research since their discovery, which gave birth to the RNA World hypothesis and the field of ribozyme engineering. Therefore, a fundamental understanding of the chemical mechanisms of RNA catalysis is significant due to the central role RNA plays in biology, the implications it has for theories of evolution, and the insight it provides that can ultimately be used to develop new biotechnologies, diagnostic tools and medical therapies. Our lab studies small self-cleaving ribozymes that catalyze the cleavage and ligation of the RNa backbone linkage - a reaction often used in viral replication and also one that has profound implications for biomedical applications. Examples include the hammerhead, hepatitis delta virus, hairpin, and VS ribozymes, and catalytic riboswitches such as the L1 ligase and glmS ribozymes. A goal of this work is to understand general stategies and guiding principles that provide a more fundamental understanding of RNA catalysis and help facilitate discovery and design.

RNA Electrostatics and Ion Atmosphere
Unlike most proteins, RNA is a highly charged polyanion that requires stabilization by its solvation environment. In order for RNA to fold, anionic charges on different regions of RNA (separated by sequence or strand), must be brought together. Consequently, formation of tertiary contacts and the stabilization of different RNA folds is highly sensitive to the ion atmosphere around RNA. It is a goal of our research lab to provide a fundamental, predictive understanding of RNA electrostatics and ion atmosphere, and its structural and thermodynamic consequences on folding.