Molecular driving forces defining lipid positions around aquaporin-0
Molecular driving forces defining lipid positions around aquaporin-0
复制标题
DOI：
10.1073/pnas.1121054109
复制
发表时间：
2012-06-19
影响因子：
11.1
通讯作者：
de Groot, Bert L.
中科院分区：
文献类型：
--
作者：
Aponte-Santamaria, Camilo;Briones, Rodolfo;de Groot, Bert L.
脂质-蛋白质相互作用在生物膜中起着关键作用。晶状体特异性水通道水通道蛋白0（AQP 0）的电子晶体学研究揭示了这种相互作用的原子观点，通过提供高分辨率的环状脂质AQP 0周围的结构。然而，目前还不清楚这些脂质结构是否代表了单个蛋白质周围不受约束的脂质的位置，以及什么分子决定因素定义了AQP 0周围的脂质位置。我们解决了这些问题，通过使用分子动力学模拟和晶体学细化，并计算时间平均密度的二肉豆蔻酰磷脂酰胆碱脂质AQP 0周围。我们的模拟表明，虽然实验确定的晶体脂质位置的晶体包装的约束，他们适当地描述了一个人的AQP 0四聚体周围的不受约束的脂质的行为，因此可能代表生理相关的脂质位置。虽然酰基链被很好地定位，但脂质头部基团没有。此外，计算机模拟突变表明，静电相互作用不发挥主要作用，吸引这些磷脂对AQP 0。相反，蛋白质的流动性至关重要地调节脂质定位，并解释了细胞外和细胞质小叶之间的脂质密度差异。此外，我们的模拟支持一个一般的机制，其中膜蛋白横向扩散伴随着几层本地化的脂质，与环状脂质的位置受到影响最大的蛋白质表面。我们的结论是，酰基链，而不是头部基团定义的位置，二肉豆蔻酰磷脂酰胆碱脂质AQP 0周围。脂质定位在很大程度上取决于蛋白质表面的流动性，而氢键起着重要但次要的作用。
Lipid-protein interactions play pivotal roles in biological membranes. Electron crystallographic studies of the lens-specific water channel aquaporin-0 (AQP0) revealed atomistic views of such interactions, by providing high-resolution structures of annular lipids surrounding AQP0. It remained unclear, however, whether these lipid structures are representative of the positions of unconstrained lipids surrounding an individual protein, and what molecular determinants define the lipid positions around AQP0. We addressed these questions by using molecular dynamics simulations and crystallographic refinement, and calculated time-averaged densities of dimyristoyl-phosphatidylcholine lipids around AQP0. Our simulations demonstrate that, although the experimentally determined crystallographic lipid positions are constrained by the crystal packing, they appropriately describe the behavior of unconstrained lipids around an individual AQP0 tetramer, and thus likely represent physiologically relevant lipid positions. While the acyl chains were well localized, the lipid head groups were not. Furthermore, in silico mutations showed that electrostatic inter actions do not play a major role attracting these phospholipids towards AQP0. Instead, the mobility of the protein crucially modulates the lipid localization and explains the difference in lipid density between extracellular and cytoplasmic leaflets. Moreover, our simulations support a general mechanism in which membrane proteins laterally diffuse accompanied by several layers of localized lipids, with the positions of the annular lipids being influenced the most by the protein surface. We conclude that the acyl chains rather than the head groups define the positions of dimyristoyl-phosphatidylcholine lipids around AQP0. Lipid localization is largely determined by the mobility of the protein surface, whereas hydrogen bonds play an important but secondary role.