Volatile anesthetic binding to proteins is influenced by solvent and aliphatic residues.
Volatile anesthetic binding to proteins is influenced by solvent and aliphatic residues.
复制标题
挥发性麻醉剂与蛋白质的结合受溶剂和脂肪族残留物的影响。
DOI：
10.1021/ci800206a
复制
发表时间：
2008
影响因子：
5.6
通讯作者：
Jones,KeithA
中科院分区：
文献类型：
--
作者：
Streiff,JohnH;Jones,KeithA
这项工作的主要目的是表征多种麻醉靶蛋白中的VA结合位点。一种计算算法被用来量化VA结合蛋白结构中的两亲口袋的溶剂排斥和脂肪族特性。蛋白质结构中的VA结合位点被定义为具有溶剂排斥和脂肪族特征的口袋，其超过在血清白蛋白、萤火虫荧光素酶和脱铁铁蛋白的VA结合位点中观察到的最小值。我们发现，VA结合蛋白的结构在这些口袋中富集，并且预测的结合位点与实验确定的几种蛋白质的结合位置一致。使用Autodock 3将模拟分子1，1，1，2，2-五氟乙烷、二氟甲基1，1，1，2-三氟乙基醚和七氟烷以及氟烷和异氟烷的异构体对接到这些潜在的结合位点。我们发现，各种VA分子的两亲性口袋的结合主要是由VDW相互作用，并在较小程度上由弱氢键和静电相互作用驱动。此外，Δ G结合值的趋势遵循Meyer-Overton规则。这些结果表明，VA效力与VA配体和蛋白质靶标之间的VDW相互作用有关。这是可能的，VA绑定到网站具有高度的溶剂排斥和脂肪族字符，因为脂肪族残基提供了有利的VDW接触和弱氢键供体。占据这些位点的水分子保持口袋完整性，与VA配体缔合，并减少VA的不利溶剂化焓。通过VA配体置换到本体中的水分子可以为VA结合提供额外的有利的疏水贡献。麻醉是许多健康相关程序的组成部分，其结果可以通过更好地了解麻醉作用的分子靶点和机制来改善。
The main objective of this work was to characterize VA binding sites in multiple anesthetic target proteins. A computational algorithm was used to quantify the solvent exclusion and aliphatic character of amphiphilic pockets in the structures of VA binding proteins. VA binding sites in the protein structures were defined as the pockets with solvent exclusion and aliphatic character that exceeded minimum values observed in the VA binding sites of serum albumin, firefly luciferase, and apoferritin. We found that the structures of VA binding proteins are enriched in these pockets and that the predicted binding sites were consistent with experimental determined binding locations in several proteins. Autodock3 was used to dock the simulated molecules of 1,1,1,2,2-pentafluoroethane, difluoromethyl 1,1,1,2-tetrafluoroethyl ether, and sevoflurane and the isomers of halothane and isoflurane into these potential binding sites. We found that the binding of the various VA molecules to the amphiphilic pockets is driven primarily by VDW interactions and to a lesser extent by weak hydrogen bonding and electrostatic interactions. In addition, the trend in ΔGbindingvalues follows the Meyer-Overton rule. These results suggest that VA potencies are related to the VDW interactions between the VA ligand and protein target. It is likely that VA bind to sites with a high degree of solvent exclusion and aliphatic character because aliphatic residues provide favorable VDW contacts and weak hydrogen bond donors. Water molecules occupying these sites maintain pocket integrity, associate with the VA ligand, and diminish the unfavorable solvation enthalpy of the VA. Water molecules displaced into the bulk by the VA ligand may provide an additional favorable enthalpic contribution to VA binding. Anesthesia is a component of many health related procedures, the outcomes of which could be improved with a better understanding of the molecular targets and mechanisms of anesthetic action.