Background

Previous studies found that Vitamin E (VE) could recruit protein kinase B (Akt1) to the membrane by targeting its unconventional lipid-binding site, which led to the dephosphorylation of Akt1 at Ser473, eventually deactivating the enzyme.

Methods

A series of VE-like compounds with varying types and lengths of the linker groups are designed to study the VE-driven membrane recruitment of Akt1 using a combined molecular docking and molecular dynamics (MD) simulation approach.

Results

We find that the linker groups with only one methylene linker and multiple hydrogen bond donors are optimal for achieving a balance between binding to the protein and partitioning into the membrane to form a stable protein-ligand-membrane ternary complex. These polar linkers are found to form stable hydrogen bonds with the lipid head groups during the MD simulations, which turns out critical for ensuring that the chromanol ring of the VE-like compounds resides above the membrane surface to fully engage in the protein.

Conclusions

Our results reveal the molecular determinants of the linker groups for VE derivatives' ability to anchor Akt1 to the membrane.

General significance

These findings will facilitate the design of membrane interfacial compounds to recruit specific proteins to the membrane to modulate the protein function.

中文翻译：

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计算研究维生素E衍生物中极性连接子对膜募集的影响。

背景

先前的研究发现，维生素E（VE）可以通过靶向其非常规脂质结合位点而将蛋白激酶B（Akt1）募集到膜上，从而导致Ser473处Akt1的去磷酸化，最终使该酶失活。

方法

设计了一系列具有不同类型和长度的连接基团的VE样化合物，以结合分子对接和分子动力学（MD）模拟方法研究VE驱动的Akt1膜募集。

结果

我们发现，仅具有一个亚甲基接头和多个氢键供体的接头基团对于实现与蛋白质的结合与分配到膜之间以形成稳定的蛋白质-配体-膜三元复合物之间的平衡是最佳的。发现这些极性连接基在MD模拟过程中与脂质头基团形成稳定的氢键，这对于确保VE样化合物的苯甲酚环位于膜表面上方以完全参与蛋白质至关重要。

结论

我们的结果揭示了VE衍生物将Akt1锚定在膜上的能力的连接基团的分子决定因素。

一般意义

这些发现将有助于膜界面化合物的设计，以将特定蛋白募集到膜上以调节蛋白功能。