Dissecting the Hydrophobic Effect on the Molecular Level: The Role of Water, Enthalpy, and Entropy in Ligand Binding to Thermolysin
Dissecting the Hydrophobic Effect on the Molecular Level: The Role of Water, Enthalpy, and Entropy in Ligand Binding to Thermolysin
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DOI：
10.1002/anie.201208561
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发表时间：
2013-01-01
影响因子：
16.6
通讯作者：
Klebe, Gerhard
中科院分区：
文献类型：
--
作者：
Biela, Adam;Nasief, Nader N.;Klebe, Gerhard
疏水效应被认为是通过将水分子从形成的界面排除而使具有扩展的亲脂性分子表面的非极性物质在水溶液中聚集的驱动力。[1，2]它通常被引用来解释为什么油/水混合物会自发分离，为什么可溶性蛋白质会以疏水核心和亲水外表面折叠，[3，4]为什么膜组分会组装成脂质双层和胶束，为什么膜蛋白会容纳在膜片段中，以及为什么小分子会在疏水表面相互掩埋的蛋白结合口袋中结合。[5]在后一种情况下，药物化学中的一般策略是通过增加配体的疏水表面来改善蛋白质-配体结合，所述配体的疏水表面被埋在靶蛋白的疏水口袋中。在所有情况下，疏水效应被认为是缔合的主要力。在分子水平上，这种现象通常归因于疏水表面周围排列的水分子的位移，并且熵效应负责驱动这种缔合。的熵配置文件是有关的有序度和水分子的动态特性的变化，这被认为是更无序的散装水相相对于它们位于被取代后，疏水缔合之前。然而，最近的研究表明，疏水性相互作用可以来自于疏水性或熵驱动的结合，使得通常对疏水效应的简单解释是不够的。[6-12]在计算设计工具中，显式水分子的处理也得到了越来越多的认可。WaterMap和Szmap [13，14]等工具试图在药物设计中考虑水的结构，并根据焓和熵讨论单个水分子的性质。为了更好地理解分子水平上的疏水效应及其在蛋白质-配体结合中的作用，我们开始以嗜热菌蛋白酶（TLN）为模型系统进行系统研究。[6]这种来自热蛋白水解芽孢杆菌的热稳定细菌锌金属蛋白酶表现出三个主要疏水性质的特异性口袋（示意图1）。它一直被认为
The hydrophobic effect is viewed as the driving force for the aggregation of nonpolar substances with extended lipophilic molecular surfaces in aqueous solution through the exclusion of water molecules from the formed interfaces.[1, 2] It is usually quoted to explain why an oil/water mixture spontaneously separates, why soluble proteins fold with a hydrophobic core and a hydrophilic outer surface,[3, 4] why membrane components assemble as lipid bilayers and micelles, why membrane proteins are accommodated in membrane segments, and why small molecules associate in protein binding pockets with mutual burial of hydrophobic surfaces.[5] In the latter instance, it is a general strategy in medicinal chemistry to improve protein–ligand binding by increasing the ligand s hydrophobic surface which becomes buried in hydrophobic pockets of the target protein. In all cases, the hydrophobic effect is considered to be the major force of association. On the molecular level, this phenomenon is commonly attributed to the displacement of water molecules arranged around the hydrophobic surfaces, and entropic effects are made responsible to drive this association. The entropic profile is related to changes in the degree of ordering and the dynamic properties of the water molecules, which are assumed to be more disordered in the bulk water phase relative to where they were located prior to being displaced upon hydrophobic association. Recent studies have demonstrated, however, that hydrophobic interactions can originate either from enthalpyor entropy-driven binding, making simple explanations often presented for the hydrophobic effect insufficient.[6–12] Also in computational design tools the handling of explicit water molecules has received increasing recognition. Tools such as WaterMap and Szmap [13, 14] try to take into account water structures in drug design and the properties of individual water molecules are discussed in terms of enthalpy and entropy.In order to obtain a better understanding of the hydrophobic effect on the molecular level and its role in protein–ligand binding, we embarked on a systematic study using thermolysin (TLN) as a model system.[6] This thermostable bacterial zinc metalloprotease from Bacillus thermoproteolyticus exhibits three specificity pockets of predominantly hydrophobic nature (Scheme1). It has been considered