Modeling of annexin A2-Membrane interactions by molecular dynamics simulations.
Modeling of annexin A2-Membrane interactions by molecular dynamics simulations.
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DOI：
10.1371/journal.pone.0185440
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Heuer A
中科院分区：
文献类型：
--
作者：
Hakobyan D;Gerke V;Heuer A
膜联蛋白是Ca2+调控的磷脂结合蛋白家族，参与膜结构域组织和膜运输。虽然它们被广泛研究，并且几种可溶性膜联蛋白的晶体结构可用，但它们的膜结合模式从未在分子水平上研究过。在这里，我们通过分子动力学模拟获得了膜联-膜相互作用的分子信息，可以作为胞质蛋白外周膜结合的范例。我们分析了含有单体膜联蛋白A2 （AnxA2）的系统，这是一种带负电荷的磷脂酰丝氨酸（POPS）脂质以及Ca2+离子的膜。在原子水平上，我们确定了与Ca2+离子和膜表现出最强相互作用的AnxA2取向和各自的残基。模拟结果与早期关于结合Ca2+离子定位的实验结果完全一致。此外，我们首次发现蛋白质的赖氨酸残基与POPS脂质之间的显著相互作用独立于Ca2+发生，这表明anxa2 -膜相互作用也可以在低Ca2+环境中发生。最后，在我们的模拟中，通过改变Ca2+浓度和脂质组成，我们观察到钙诱导的膜负曲率以及anxa2诱导的脂质排序。
The annexins are a family of Ca2+-regulated phospholipid binding proteins that are involved in membrane domain organization and membrane trafficking. Although they are widely studied and crystal structures are available for several soluble annexins their mode of membrane association has never been studied at the molecular level. Here we obtained molecular information on the annexin-membrane interaction that could serve as paradigm for the peripheral membrane association of cytosolic proteins by Molecular Dynamics simulations. We analyzed systems containing the monomeric annexin A2 (AnxA2), a membrane with negatively charged phosphatidylserine (POPS) lipids as well as Ca2+ ions. On the atomic level we identify the AnxA2 orientations and the respective residues which display the strongest interaction with Ca2+ ions and the membrane. The simulation results fully agree with earlier experimental findings concerning the positioning of bound Ca2+ ions. Furthermore, we identify for the first time a significant interaction between lysine residues of the protein and POPS lipids that occurs independently of Ca2+ suggesting that AnxA2-membrane interactions can also occur in a low Ca2+ environment. Finally, by varying Ca2+ concentrations and lipid composition in our simulations we observe a calcium-induced negative curvature of the membrane as well as an AnxA2-induced lipid ordering.
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