Levina Elena O, Khrenova Maria G, Astakhov Andrey A, Tsirelson Vladimir G
Federal Research Centre "Fundamentals of Biotechnology" of the Russian Academy of Sciences Moscow Russia
Moscow Institute of Physics and Technology Dolgoprudny Russia.
RSC Adv. 2020 Feb 27;10(15):8664-8676. doi: 10.1039/c9ra10649a.
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-β-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[double bond, length as m-dash]C double bond in its N-C-C fragment. The temporary N⋯H-O 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 N⋯H-O fragment control electron lone pair localization. Delocalization tensor, linear response kernel and source function indicate that features of electron delocalization in the N-C-C fragment of cephalosporins in the transition state complexes determine the differences in C-C bond for substrates with high and low rate constants. The C-C bond of the N-C-C 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.
进行QM/MM模拟并随后进行电子密度特征分析，以加深对L1金属β-内酰胺酶活性位点中头孢菌素水解反应机制的理解。通过使用一组扩展的键合描述符来解释十种相似头孢菌素化合物反应性的差异。反应的限速步骤的特征是质子转移到头孢菌素噻嗪环的氮原子上，并伴随着其N-C-C片段中C=C双键的形成。在反应限速步骤的过渡态中形成的临时N⋯H-O氢键被认为是控制各种头孢菌素反应性的关键原子相互作用。非局部实空间键合描述符表明，过渡态中N原子上孤对电子的不同局域化程度会影响化合物的反应性：反应性较低的物种通常电子局域化程度较小。特别是，费米空穴分析显示了N⋯H-O片段中的交换电子相关性如何控制电子孤对的局域化。离域张量、线性响应核和源函数表明，过渡态络合物中头孢菌素N-C-C片段的电子离域特征决定了具有高和低速率常数的底物的C-C键差异。对于反应性较低的物种，过渡态下N-C-C片段的C-C键与前一个中间体的C-C键相似，而对于反应性较高的化合物，则类似于酶-产物复合物的特征。讨论了用于解决该问题的描述符的优点和局限性，并强调了该方法的通用性。
