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Magnesium-Dependent Active-Site Conformational Selection in the Diels−Alderase Ribozyme

机译:Diels-Alderase核酶中镁依赖性活性位点构象选择

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摘要

The Diels−Alderase ribozyme, an in vitro-evolved ribonucleic acid enzyme, accelerates the formation of carbon−carbon bonds between an anthracene diene and a maleimide dienophile in a [4 + 2] cycloaddition, a reaction with broad application in organic chemistry. Here, the Diels−Alderase ribozyme is examined via molecular dynamics (MD) simulations in both crystalline and aqueous solution environments. The simulations indicate that the catalytic pocket is highly dynamic. At low Mg2+ ion concentrations, inactive states with the catalytic pocket closed dominate. Stabilization of the enzymatically active, open state of the catalytic pocket requires a high concentration of Mg2+ ions (e.g., 54 mM), with cations binding to specific phosphate sites on the backbone of the residues bridging the opposite strands of the pocket. The free energy profile for pocket opening at high Mg2+ cation concentration exhibits a double minimum, with a barrier to opening of 5.5 kJ/mol and the closed state 3 kJ/mol lower than the open state. Selection of the open state on substrate binding leads to the catalytic activity of the ribozyme. The simulation results explain structurally the experimental observation that full catalytic activity depends on the Mg2+ ion concentration.
机译:Diels-Alderase核酶是一种体外进化的核糖核酸酶,可在[4 + 2]环加成反应中加快蒽二烯与马来酰亚胺二烯亲和体之间碳-碳键的形成,该反应在有机化学中得到了广泛应用。在这里,Diels-Alderase核酶通过结晶和水溶液环境中的分子动力学(MD)模拟进行检查。仿真表明催化袋是高度动态的。在低的Mg 2 + 离子浓度下,催化袋关闭的非活性状态占主导。稳定催化口袋的酶促活性,打开状态需要高浓度的Mg 2 + 离子(例如54 mM),且阳离子与残基主链上特定的磷酸酯位点结合,从而桥接口袋的相反两股。在高Mg 2 + 阳离子浓度下,口袋开放的自由能分布呈现出两倍的最小值,其开放势垒为5.5 kJ / mol,闭合态比开放态低3 kJ / mol。在底物结合上的开放状态的选择导致核酶的催化活性。模拟结果从结构上解释了实验观察结果,即完全催化活性取决于Mg 2 + 离子浓度。

著录项

  • 来源
    《Journal of the American Chemical Society》 |2010年第36期|p.12587-12596|共10页
  • 作者

    Tomasz Bereźniak;

  • 作者单位

    Computational Molecular Biophysics, IWR, University of Heidelberg, Im Neuenheimer Feld 368, 69120 Heidelberg, Germany, Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany, and Oak;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

  • 入库时间 2022-08-18 00:50:20

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