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首页> 外文期刊>Biochemistry >Hydrogen Bonding in the Active Site of Ketosteroid Isomerase: Electronic Inductive Effects and Hydrogen Bond Coupling
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Hydrogen Bonding in the Active Site of Ketosteroid Isomerase: Electronic Inductive Effects and Hydrogen Bond Coupling

机译：酮固醇异构酶活性位点中的氢键：电子感应效应和氢键耦合。

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Computational studies are performed to analyze the physical properties of hydrogen bondsndonated by Tyr16 and Asp103 to a series of substituted phenolate inhibitors bound in the active site ofnketosteroid isomerase (KSI). As the solution pKa of the phenolate increases, these hydrogen bond distancesndecrease, the associated nuclear magnetic resonance (NMR) chemical shifts increase, and the fraction ofnprotonated inhibitor increases, in agreement with prior experiments. The quantum mechanical/molecularnmechanical calculations provide insight into the electronic inductive effects along the hydrogen bondingnnetwork that includes Tyr16, Tyr57, and Tyr32, as well as insight into hydrogen bond coupling in the activensite. The calculations predict that the most-downfield NMR chemical shift observed experimentallyncorresponds to the Tyr16-phenolate hydrogen bond and that Tyr16 is the proton donor when a boundnnaphtholate inhibitor is observed to be protonated in electronic absorption experiments. According to thesencalculations, the electronic inductive effects along the hydrogen bonding network of tyrosines cause the Tyr16nhydroxyl to bemore acidic than theAsp103 carboxylic acidmoiety, which is immersed in a relatively nonpolarnenvironment. When one of the distal tyrosine residues in the network is mutated to phenylalanine, therebyndiminishing this inductive effect, the Tyr16-phenolate hydrogen bond becomes longer and the Asp103-phe-nnolate hydrogen bond shorter, as observed in NMR experiments. Furthermore, the calculations suggest thatnthe differences in the experimental NMR data and electronic absorption spectra for pKSI and tKSI, twonhomologous bacterial forms of the enzyme, are due predominantly to the third tyrosine that is present in thenhydrogen bonding network of pKSI but not tKSI. These studies also provide experimentally testablenpredictions about the impact ofmutating the distal tyrosine residues in this hydrogen bonding network on thenNMR chemical shifts and electronic absorption spectra.
机译：进行了计算研究，以分析由Tyr16和Asp103与一系列结合在酮固醇异构酶（KSI）活性位点上的取代酚盐抑制剂所键合的氢键的物理性质。随着酚盐溶液pKa的增加，这些氢键距离减少，相关的核磁共振（NMR）化学位移增加，并且质子化抑制剂的比例增加，这与先前的实验一致。量子力学/分子力学计算提供了对沿氢键合网络（包括Tyr16，Tyr57和Tyr32）的电子感应效应的了解，以及对活性位点中氢键耦合的了解。计算预测，在实验中观察到的最弱磁场NMR化学位移与Tyr16-酚盐氢键相对应，并且当在电子吸收实验中观察到联萘酚抑制剂被质子化时，Tyr16是质子供体。根据该计算，沿着酪氨酸氢键网络的电子感应效应使Tyr16n羟基比Asp103羧酸部分酸性更高，后者被浸没在相对非极性的环境中。当在网络中的远端酪氨酸残基之一突变为苯丙氨酸时，从而减弱了这种诱导效应，如NMR实验所观察到的，Tyr16-苯酚酸酯的氢键变长，而Asp103-phe-壬酸酯的氢键变短。此外，计算表明，pKSI和tKSI（酶的两种同源细菌形式）的实验NMR数据和电子吸收光谱的差异主要是由于存在于pKSI的氢键网络中的第三酪氨酸引起的，而不是tKSI的氢。这些研究还提供了有关该氢键网络中远端酪氨酸残基突变对NMR化学位移和电子吸收光谱的影响的实验可检验的预测。

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  • 来源
    《Biochemistry》 |2010年第48期|p.10339-10348|共10页
  • 作者

    Philip Hanoian Paul A. Sigala Daniel Herschlag and Sharon Hammes-Schiffer;

  • 作者单位

    ‡Department of Chemistry, 104 Chemistry Building, Pennsylvania State University, University Park, Pennsylvania 16802,United States, and §Department of Biochemistry, Stanford University, Stanford, California 94305-5080, United States.) Present address: Department of Molecular Microbiology, Washington University, St. Louis, MO 63110.;

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