J Chem Theory Comput. 2019 Feb 12;15(2):1418-1429. doi: 10.1021/acs.jctc.8b00945. Epub 2019 Jan 29.
The amphipathic lipid packing sensor (ALPS) motif, originally discovered on the ArfGAP1 membrane-binding protein, binds to pre-existing large packing defects in a membrane (spontaneous or due to membrane curvature), though a more precise relationship between the ALPS peptide and packing defect characteristics of a membrane remains unclear. We developed an image processing technique for identifying packing defects to quantify the relationship between the ALPS peptide of the Osh4 protein in yeast and packing defects on a membrane model using molecular dynamics simulations. We used the highly mobile membrane mimetic (HMMM) model to create very large packing defects and expedite the binding time scale. Most prominently, we show that the probability of the ALPS peptide moving toward the membrane increases when it is near a large packing defect. Deviations from this trend exist for very large packing defects (≳115 Å), which we propose is due to an overwhelming hydrophobic effect and a reduced electrostatic effect when large portions of the nonpolar core are exposed and the peptide is oriented unfavorably. Furthermore, we compared our HMMM results to similar simulations using all-atom lipid membranes. The binding time scales of the ALPS peptide can be reduced by roughly 1 order of magnitude when HMMM is used, while still maintaining many of the important physical characteristics of the binding process observed when using an all-atom lipid membrane.
两亲性脂质堆积传感器（ALPS）基序最初在 ArfGAP1 膜结合蛋白上被发现，它与膜中的预先存在的大堆积缺陷结合（自发的或由于膜曲率），尽管 ALPS 肽与膜堆积缺陷特征之间的更精确关系仍不清楚。我们开发了一种图像处理技术来识别堆积缺陷，以使用分子动力学模拟来定量酵母中 Osh4 蛋白的 ALPS 肽与膜模型上的堆积缺陷之间的关系。我们使用高迁移性膜模拟物（HMMM）模型来创建非常大的堆积缺陷，并加快结合的时间尺度。最显著的是，我们表明当 ALPS 肽靠近大堆积缺陷时，其向膜移动的概率增加。对于非常大的堆积缺陷（≳115 Å），存在偏离这种趋势的情况，我们提出这是由于当大部分非极性核心暴露并且肽不利地定向时，疏水作用压倒一切并且静电作用降低。此外，我们将我们的 HMMM 结果与使用全原子脂质膜的类似模拟进行了比较。当使用 HMMM 时，ALPS 肽的结合时间尺度可以降低约 1 个数量级，同时仍保持使用全原子脂质膜观察到的结合过程的许多重要物理特性。
