Modeling the membrane binding mechanism of a lipid transport protein Osh4 to single membranes
Modeling the membrane binding mechanism of a lipid transport protein Osh4 to single membranes
复制标题
模拟脂质转运蛋白 Osh4 与单膜的膜结合机制
DOI：
10.1016/j.bpj.2022.03.001
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发表时间：
2022
影响因子：
3.4
通讯作者：
Klauda, Jeffery B.
中科院分区：
文献类型：
--
作者：
Karmakar, Sharmistha;Klauda, Jeffery B.
利用全原子（AA）分子动力学模拟揭示了酵母氧甾醇结合蛋白（Osh4）的结合机制，利用AA和高移动膜模拟（HMMM）表征来模拟具有不同阴离子脂质浓度的膜。对于某些蛋白质-脂质相互作用，使用改进的力场描述（CUFIX）来准确描述脂质-蛋白质静电相互作用。我们详细的计算研究已经确定了一个单一的，β-折痕取向的，Osh4的膜结合构象为所有阴离子膜。ph -239残基在膜磷酸盐平面下方的渗透是Osh4膜结合状态的特征标志。当苯丙氨酸环深深地固定在膜上时；Osh4的其他区域，即ALPS基序、β6- β7环、β14- β15环和β16- β17环，最大限度地与膜接触。此外，松散的脂质堆积和HMMM的高迁移率使得ALPS基序通过其疏水表面与膜脂结合更强。在HMMM转换为AA并平衡后，与AA表示开始的模拟相比，结合强度要强两到三倍，这表明ALPS基序对结合的重要性。结合能的定量估计表明，苯丙氨酸环在Osh4稳定的膜附着中起着至关重要的作用，并对整个结合过程起着重要作用。CUFIX参数提供了蛋白质与膜之间疏水和静电相互作用的更平衡的图像，这与我们过去的工作不同，表明盐桥单独稳定了osh4膜的接触。我们的研究提供了Osh4与模型单膜结合机制的全面图景，因此，了解初始相互作用对于阐明该蛋白在细胞器之间输送脂质的生物学功能非常重要。
All-atom (AA) molecular dynamics simulations are used to unravel the binding mechanism of yeast oxysterol binding protein (Osh4) to model membranes with varying anionic lipid concentration using AA and the highly mobile membrane mimetic (HMMM) representations. For certain protein-lipid interactions, an improved forcefield description is used (CUFIX) to accurately describe lipid-protein electrostatic interactions. Our detailed computational studies have identified a single, β-crease oriented, membrane-bound conformation of Osh4 for all anionic membranes. The penetration of the PHE-239 residue below the membrane phosphate plane is the characteristic signature of the membrane-bound state of Osh4. As the phenylalanine loop anchors itself deeply in the membrane; the other regions of the Osh4, namely, ALPS motif, β6- β7 loop, β14- β15 loop, and β16- β17 loop, maximize their contact with the membrane. Furthermore, loose lipid packing and higher mobility of HMMM enable stronger association of the ALPS motif with the membrane lipids through its hydrophobic surface. After the HMMM is converted to AA and equilibrated, the binding is two to three times stronger compared with simulations started with the AA representation, yielding the major importance of the ALPS motif to binding. Quantitative estimation of binding energy revealed that the phenylalanine loop plays a crucial role in stable membrane attachment of Osh4 and contributes significantly toward overall binding process. The CUFIX parameters provide a more balanced picture of hydrophobic and electrostatic interactions between the protein and the membrane, which differs from our past work that showed salt bridges alone stabilized Osh4-membrane contact. Our study provides a comprehensive picture of the binding mechanism of Osh4 with model single membranes and, thus, understanding of the initial interactions is important for elucidating the biological function of this protein to shuttle lipids between organelles.