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首页> 外文期刊>Biochemistry >Inverse Thio Effects in the Hepatitis Delta Virus Ribozyme Reveal that the Reaction Pathway Is Controlled by Metal Ion Charge Density
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Inverse Thio Effects in the Hepatitis Delta Virus Ribozyme Reveal that the Reaction Pathway Is Controlled by Metal Ion Charge Density

机译：肝炎δ病毒核酶中的逆硫化疗法表明，反应途径由金属离子电荷密度控制

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摘要

The hepatitis delta virus (HDV) ribozyme self-cleaves in the presence of a wide range of monovalent and divalent ions. Prior theoretical studies provided evidence that self-cleavage proceeds via a concerted or stepwise pathway, with the outcome dictated by the valency of the metal ion. In the present study, we measure stereospecific thio effects at the nonbridging oxygens of the scissile phosphate under a wide range of experimental conditions, including varying concentrations of diverse monovalent and divalent ions, and combine these with quantum mechanical/molecular mechanical (QM/MM) free energy simulations on the stereospecific thio substrates. The R-P substrate gives large normal thio effects in the presence of all monovalent ions. The SP substrate also gives normal or no thio effects, but only for smaller monovalent and divalent cations, such as Li+, Mg2+, Ca2+, and Sr2+; in contrast, sizable inverse thio effects are found for larger monovalent and divalent cations, including Na+, K+, NH4+, and Ba2+. Proton inventories are found to be unity in the presence of the larger monovalent and divalent ions, but two in the presence of Mg2+. Additionally, ratepH profiles are inverted for the low charge density ions, and only imidazole plus ammonium ions rescue an inactive C75 Delta variant in the absence of Mg2+. Results from the thio effect experiments, ratepH profiles, proton inventories, and ammonium/imidazole rescue experiments, combined with QM/MM free energy simulations, support a change in the mechanism of HDV ribozyme self-cleavage from concerted and metal ion-stabilized to stepwise and proton transfer-stabilized as the charge density of the metal ion decreases.
机译：肝炎δ病毒（HDV）核酶在各种单价和二价离子存在下自切割。在理论研究提供了证据表明，自我乳化通过齐心或逐步的途径进行，该途径由金属离子的级别决定。在本研究中，我们测量在宽范围的实验条件下剪磷酸盐的非录音氧化剂的立体特异性硫醚效应，包括不同浓度的多元价和二价管离子，并用量子机械/分子机械（QM / mm）结合这些立体特异性硫型底座的自由能量模拟。 R-P底物在所有单价离子存在下赋予大规模的正常抗疗效。 SP底物还给出正常或没有硫型效应，但仅适用于较小的单价和二价阳离子，例如Li +，Mg2 +，Ca2 +和SR2 +;相比之下，发现较大的一价和二价阳离子，包括Na +，K +，NH 4 +和Ba2 +。在较大的单价和二价离子存在下，发现质子清单是统一的，而是在Mg 2 +存在下的两个。另外，对于低电荷密度离子反转速率曲线，并且仅在不存在Mg2 +的情况下才拯救咪唑加铵离子的亚咪唑加铵离子。噻虫效应实验，速率曲线，质子库存和铵/咪唑救援实验结果，与QM / MM自由能模拟相结合，支持HDV核酶自切割机制从互联网稳定的HDV核酶自切割机理的变化随着金属离子的电荷密度降低，质子转移稳定。

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