Insight into the Role of Mg2+ in Hammerhead Ribozyme Catalysis from X-ray Crystallography and Molecular Dynamics Simulation

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• 作者：Tai-Sung Lee ; Carlos Silva-L&oacute ; pez ; MonikaMartick ; William G. Scott ; Darrin M. York
• 刊名：Journal of Chemical Theory and Computation
• 出版年：2007
• 出版时间：March 2007
• 年：2007
• 卷：3
• 期：2
• 页码：325 - 327
• 全文大小：99K
• 年卷期：v.3,no.2(March 2007)
• ISSN：1549-9626

文摘

Results of a series of 12 ns molecular dynamics(MD) simulations of the reactant state (with and without aMg²⁺ ion) and early and late transition state mimics arepresented based on a recently reported crystal structureof a full-length hammerhead RNA. The simulation resultssupport a catalytically active conformation with a Mg²⁺ ionbridging the A9 and scissile phosphates. In the reactantstate, the Mg²⁺ spends significant time closely associatedwith the 2'OH of G8 but remains fairly distant from theleaving group O_5' position. In the early TS mimic simulation,where the nucleophilic O_2' and leaving group O_5' areequidistant from the phosphorus, the Mg²⁺ ion remainstightly coordinated to the 2'OH of G8 but is positionedcloser to the O_5' leaving group, stabilizing the accumulatingcharge. In the late TS mimic simulation, the coordinationaround the bridging Mg²⁺ ion undergoes a transitionwhereby the coordination with the 2'OH of G8 is replacedby the leaving group O_5' that has developed significantcharge. At the same time, the 2'OH of G8 forms ahydrogen bond with the leaving group O_5' and is positionedto act as a general acid catalyst. This work represents thefirst reported simulations of the full-length hammerheadstructure and TS mimics and provides direct evidence forthe possible role of a bridging Mg²⁺ ion in catalysis that isconsistent with both crystallographic and biochemical data.