Free-energy relationships for the interactions of tryptophan with phosphocholines
Free-energy relationships for the interactions of tryptophan with phosphocholines
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DOI：
10.1039/b913919b
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发表时间：
2009-01-01
影响因子：
3.2
通讯作者：
Wilson, Mark R.
中科院分区：
文献类型：
--
作者：
Blaser, Georg;Sanderson, John M.;Wilson, Mark R.
在膜蛋白和多肽中，色氨酸明显倾向于出现在与脂质双层的界面区域相对应的位置。静电、偶极、疏水和构象效应对色氨酸与脂类相互作用的相对贡献一直是人们猜测的主题。为了阐明在没有蛋白质构象和膜扰动等竞争因素的情况下色氨酸-磷胆碱相互作用的基本性质，我们用核磁共振滴定方法测定了一系列色氨酸类似物在重氯仿中与1，2-二肉豆蔻基-sn-甘油-3-磷酸胆碱(DMPC)的结合特征。使用结合模型分析数据，该结合模型包括脂类聚集和水与脂类的显式关联。对于吲哚环5位上的一系列取代基(OMe、Me、H、F、Cl、BrI、NO2)，形成1：1和1：2脂-色氨酸加合物的结合自由能的趋势都遵循与相应的Para-Hammett参数有关的倒U关系，其中色氨酸(R=H)的结合最弱。这些趋势与吲哚侧链参与氢键和阳离子-pi相互作用是一致的。在显式氯仿溶剂模型中对色氨酸和DMPC进行的分子动力学模拟表明，对于脂质-色氨酸加合物的形成，结合主要是通过与胆碱氨基的羰基-阳离子和阳离子-pi相互作用以及与脂质磷酸盐的氢键相互作用来驱动的。其中一些相互作用是协同作用的，这可能解释了观察到的自由能趋势。
In membrane proteins and peptides, tryptophan exhibits a marked tendency to occur in locations that correspond to the interfacial region of the lipid bilayer. The relative contributions of electrostatic, dipolar, hydrophobic and conformational effects on the interactions of tryptophan with lipids have been the subject of much speculation. In order to elucidate the fundamental properties of tryptophan-phosphocholine interactions in the absence of competing factors such as protein conformation and membrane perturbation, we have determined the binding characteristics of a homologous series of tryptophan analogues to 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) in deuterochloroform using NMR titrimetric approaches. The data are analysed using a binding model that includes lipid aggregation and the explicit association of water with the lipid. For a series of substituents (OMe, Me, H, F, Cl, Br, I, NO2) at the 5-position of the indole ring, the trends in the free energy of association for the formation of 1 : 1 and 1 : 2 lipid-tryptophan adducts both follow an inverted-U relationship as a function of the corresponding para-Hammett parameter, with tryptophan (R = H) exhibiting the weakest binding. These trends are shown to be consistent with participation of the indole side chain in both hydrogen bonds and cation-pi interactions. Molecular dynamics simulations of tryptophan and DMPC in an explicit chloroform solvent model demonstrate that for the formation of lipid-tryptophan adducts, binding is driven predominantly by carbonyl-cation and cation-pi interactions with the choline ammonium group, alongside hydrogen bonding interactions with the lipid phosphate. Some of these interactions operate co-operatively, which may account for the observed trends in free energy.