Ganglioside-Lipid and Ganglioside-Protein Interactions Revealed by Coarse-Grained and Atomistic Molecular Dynamics Simulations.
Ganglioside-Lipid and Ganglioside-Protein Interactions Revealed by Coarse-Grained and Atomistic Molecular Dynamics Simulations.
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DOI：
10.1021/acs.jpcb.6b07142
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发表时间：
2017-04-20
期刊：
影响因子：
--
通讯作者：
Tieleman DP
中科院分区：
文献类型：
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作者：
Gu RX;Ingólfsson HI;de Vries AH;Marrink SJ;Tieleman DP
神经节苷脂是糖脂，其中含有一个或多个唾液酸的寡糖头基连接到神经酰胺。神经节苷脂存在于细胞膜的外叶，通过调节膜蛋白的结构和功能，在细胞信号转导和神经元分化等生理过程中发挥重要作用。由于神经节苷脂和蛋白质-神经节苷脂相互作用的详细行为知之甚少，我们研究了神经节苷脂GM 1和GM 3与蛋白质水通道蛋白（AQP 1）和WALP 23之间的相互作用，使用平衡分子动力学模拟和平均力计算的潜力在粗粒（CG）和原子水平。在原子模拟中，GROMOS力场的基础上，神经节苷脂聚集似乎是氢键相互作用和头基的空间位阻之间的平衡的结果。由于GM 3的头基较小，GM 3簇比GM 1簇稍大且更有序。基于Martini模型，在CG水平上没有观察到来自原子模拟的GM 1和GM 3簇的不同结构，这意味着在原子模拟和CG模拟中神经节苷脂相互作用的驱动力存在差异。对于蛋白质-神经节苷脂相互作用，在原子模拟中，GM 1脂质结合到AQP 1表面上的特定位点，而它们从WALP 23中耗尽。在CG模拟中，AQP 1表面上的神经节苷脂结合位点是相似的，但神经节苷脂聚集和蛋白质-神经节苷脂相互作用比原子模拟中更普遍。使用极化Martini水模型，结果更接近原子模拟。虽然缺乏验证的实验数据，我们提出了修改后的Martini参数神经节苷脂更紧密地模仿在原子水平上观察到的神经节苷脂簇的大小和结构。
Gangliosides are glycolipids in which an oligosaccharide headgroup containing one or more sialic acids is connected to a ceramide. Gangliosides reside in the outer leaflet of the plasma membrane and play a crucial role in various physiological processes such as cell signal transduction and neuronal differentiation by modulating structures and functions of membrane proteins. Because the detailed behavior of gangliosides and protein-ganglioside interactions are poorly known, we investigated the interactions between the gangliosides GM1 and GM3 and the proteins aquaporin (AQP1) and WALP23 using equilibrium molecular dynamics simulations and potential of mean force calculations at both coarse-grained (CG) and atomistic levels. In atomistic simulations, on the basis of the GROMOS force field, ganglioside aggregation appears to be a result of the balance between hydrogen bond interactions and steric hindrance of the headgroups. GM3 clusters are slightly larger and more ordered than GM1 clusters due to the smaller headgroup of GM3. The different structures of GM1 and GM3 clusters from atomistic simulations are not observed at the CG level based on the Martini model, implying a difference in driving forces for ganglioside interactions in atomistic and CG simulations. For protein-ganglioside interactions, in the atomistic simulations, GM1 lipids bind to specific sites on the AQP1 surface, whereas they are depleted from WALP23. In the CG simulations, the ganglioside binding sites on the AQP1 surface are similar, but ganglioside aggregation and protein-ganglioside interactions are more prevalent than in the atomistic simulations. Using the polarizable Martini water model, results were closer to the atomistic simulations. Although experimental data for validation is lacking, we proposed modified Martini parameters for gangliosides to more closely mimic the sizes and structures of ganglioside clusters observed at the atomistic level.