Insights into the Role of Conformational Transitions and Metal Ion Binding in RNA Catalysis from Molecular Simulations

Annual Reports in Computational Chemistry, Ralph A. Wheeler ed. vol. 6  p. 168-200  DOI: 10.1016/S1574-1400(10)06001-9   ISBN: 978-0-44-453552-8   Published: 2010-08-01 

Tai-Sung Lee [ ] , George M. Giambaşu, Darrin M. York [ ]

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We present a summary of recent advances in the application of molecular simulation methods to study the mechanisms of RNA catalysis. The focus of this chapter is on the nature of conformational transitions and metal ion binding on structure and activity. Two RNA enzyme systems are considered: the hammerhead ribozyme and the L1 ligase. The hammerhead ribozyme is a small archetype ribozyme that undergoes a conformational transition into a catalytically active conformation in a step that is concerted with changes in metal ion binding in the active site. The L1 ligase ribozyme is an in vitro selected ribozyme that uses a noncanonically base-paired ligation site to catalyze regioselectively and regiospecifically the 5' to 3' phosphodiester bond ligation. The L1 ligase presumably undergoes a large-scale conformational change from an inactive to an active form that involves reorientation of one of the stems by around 80 Å, making it a novel catalytic riboswitch. Analysis of the simulation results and comparison with experimental measurements provide important new insight into the conformational and chemical steps of catalysis of the hammerhead and L1 ligase ribozymes.