Binding of D- and L-captopril inhibitors to metallo-β-lactamase studied by polarizable molecular mechanics and quantum mechanics
Binding of D- and L-captopril inhibitors to metallo-β-lactamase studied by polarizable molecular mechanics and quantum mechanics
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DOI：
10.1002/jcc.10111
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发表时间：
2002-10-01
影响因子：
3
通讯作者：
Bauer, R
中科院分区：
文献类型：
--
作者：
Antony, J;Gresh, N;Bauer, R
来自B的细菌Zn 2+金属-β-内酰胺酶。fragilis是具有两个潜在金属离子结合位点的锌酶。它能裂解抗生素的内酰胺环，从而导致细菌对抗生素产生获得性耐药性。我们比较了几种可能的结合模式的巯甲丙脯酸，巯基甲酰胺抑制剂的几种锌金属酶。两个非对映异构体的卡托普利被认为是，无论是D-或L-脯氨酸残基。我们使用了极化分子力学程序SIBFA（从头计算片段之间的相互作用的总和）。考虑了两种β-内酰胺酶模型，分别包含104和188个残基。能量平衡包括分子间和分子内的相互作用能，以及溶剂化的贡献使用连续反应场程序计算。抑制剂的硫醇盐离子与两种金属离子结合。从未复合的酶中排出桥接溶剂分子。不同的竞争结合模式的卡托普利被认为是，无论是在单齿模式的抑制剂结合的锌阳离子，只有其硫醇盐离子，或在双齿模式涉及额外的锌结合其羧酸或酮羰基。抑制剂的羧酸或羰基的额外配位总是发生在锌离子处，锌离子被组氨酸、半胱氨酸和天冬氨酸侧链结合。对于两种非对映体，能量平衡有利于通过S-与卡托普利单齿结合。对双齿结合的偏好很小。相互作用能重新计算模型网站限制到卡托普利，锌离子，和他们的协调端侧链β-内酰胺酶（98个原子）。相互作用能及其在竞争排列中的排序与从头算HF和DFT程序计算的结果一致。
The bacterial Zn2+ metallo-beta-lactamase from B. fragilis is a zinc-enzyme with two potential metal ion binding sites. It cleaves the lactam ring of antibiotics, thus contributing to the acquired resistance of bacteria against antibiotics, The present study bears on the binuclear form of the enzyme. We compare several possible binding modes of captopril, a mercaptocarboxamide inhibitor of several zinc-metalloenzymes. Two diastereoisomers of captopril were considered, with either a D- or an L-proline residue. We have used the polarizable molecular mechanics procedure SIBFA (Sum of Interactions Between Fragments ab initio computed). Two beta-lactamase models were considered, encompassing 104 and 188 residues, respectively. The energy balances included the inter and intramolecular interaction energies as well as the contribution from solvation computed using a continuum reaction field procedure. The thiolate ion of the inhibitor is binding to both metal ions. expelling the bridging solvent molecule from the uncomplexed enzyme. Different competing binding modes of captopril were considered, either where the inhibitor binds in a monodentate mode to the zinc cations only with its thiolate ion, or in bidentate modes involving additional zinc binding by its carboxylate or ketone carbonyl groups. The additional coordination by the inhibitor's carboxylate or carbonyl group always occurs at the zinc ion, which is bound by a histidine, a cysteine, and an aspartate side chain, For both diastereomers, the energy balances favor monodentate binding of captopril via S-. The preference over bidentate binding is small. The interaction energies were recomputed in model sites restricted to captopril, the Zn2+ cations, and their coordinating end side chains from beta-lactamase (98 atoms). The interaction energies and their ranking among competing arrangements were consistent with those computed by ab initio HF and DFT procedures.