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首页> 外文期刊>RSC Advances >Revealing electronic features governing hydrolysis of cephalosporins in the active site of the L1 metallo-beta-lactamase
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Revealing electronic features governing hydrolysis of cephalosporins in the active site of the L1 metallo-beta-lactamase

机译：揭示L1金属β-内酰胺酶的活性位点中Cephalosporins水解的电子特征

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The QM/MM simulations followed by electron density feature analysis are carried out to deepen the understanding of the reaction mechanism of cephalosporin hydrolysis in the active site of the L1 metallo-beta-lactamase. The differences in reactivity of ten similar cephalosporin compounds are explained by using an extended set of bonding descriptors. The limiting step of the reaction is characterized by the proton transfer to the nitrogen atom of the cephalosporin thiazine ring accompanied with formation of the C-4 & xe001;C-3 double bond in its N-C-4-C-3 fragment. The temporary NMIDLINE HORIZONTAL ELLIPSISH-O-w hydrogen bond, which is formed in the transition state of the limiting step of the reaction was recognized as a key atomic interaction governing the reactivity of various cephalosporins. Non-local real-space bonding descriptors show that different extent of localization of electron lone pair at N atom in the transition state affect the reactivity of compounds: smaller electron localization is typical for the less reactive species. In particular, the Fermi hole analysis shows how exchange electron correlation in the NMIDLINE HORIZONTAL ELLIPSISH-O-w fragment control electron lone pair localization. Delocalization tensor, linear response kernel and source function indicate that features of electron delocalization in the N-C-4-C-3 fragment of cephalosporins in the transition state complexes determine the differences in C-4-C-3 bond for substrates with high and low rate constants. The C-4-C-3 bond of the N-C-4-C-3 fragment at the transition state is similar to that of the preceding intermediate for the less reactive species and resembles the features of the enzyme-product complex for more reactive compounds. The power and limitations of the descriptors applied for solving the problem are discussed and the generality of approach is stressed.
机译：进行了QM / MM模拟，然后进行电子密度特征分析，以加深对L1金属β-内酰胺酶的活性位点中的头孢菌素水解反应机制的理解。通过使用扩展的一组键合描述符解释十种类似的头孢菌素化合物的反应性的差异。反应的限制步骤的特征在于质子转移到头孢菌素噻嗪环的氮原子伴随着C-4和Xe001的形成; C-3双键在其N-C-4-C-3片段中。在反应的限制步骤的过渡状态下形成的临时Nmidline水平椭圆键合作标记为控制各种头孢菌素的反应性的关键原子相互作用。非局部实空空间键合描述符表明，在过渡状态下N原子在N原子下的电子孤立的定位程度不同影响化合物的反应性：较小的电子定位对于较少的反应性物种典型。特别地，Fermi Hole分析显示了Nmidline水平椭圆形-O-W片段控制电子孤电子孤电子化的交换电子相关性。去透明度张量，线性响应核和源功能表明，在过渡状态复合物中，在过渡状态复合物中的NC-4-C-3片段中的电子临床化的特征确定了高低低的基板的C-4-C-3键的差异速率常数。在过渡状态下Nc-4-C-3片段的C-4-C-3键类似于前述反应性物质的中间体的C-4-C-3键，并类似于酶 - 产物复合物的特征，以获得更多反应性化合物。讨论了应用于解决问题的描述符的功率和限制，并强调了方法的一般性。

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  • 来源
    《RSC Advances》 |2020年第15期|共13页
  • 作者

    Levina Elena O.; Khrenova Maria G.; Astakhov Andrey A.; Tsirelson Vladimir G.;

  • 作者单位

    Russian Acad Sci Fed Res Ctr Fundamentals Biotechnol Moscow Russia;

    Russian Acad Sci Fed Res Ctr Fundamentals Biotechnol Moscow Russia;

    Russian Acad Sci Fed Res Ctr Fundamentals Biotechnol Moscow Russia;

    Russian Acad Sci Fed Res Ctr Fundamentals Biotechnol Moscow Russia;

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