Fu Yiben, Johnson David H, Beaven Andrew H, Sodt Alexander J, Zeno Wade F, Johnson Margaret E
School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, P. R. China.
National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou 510006, P. R. China.
bioRxiv. 2024 Dec 21:2024.01.15.575755. doi: 10.1101/2024.01.15.575755.
Cytoplasmic proteins must recruit to membranes to function in processes such as endocytosis and cell division. Many of these proteins recognize not only the chemical structure of the membrane lipids, but the curvature of the surface, binding more strongly to more highly curved surfaces, or 'curvature sensing'. Curvature sensing by amphipathic helices is known to vary with membrane bending rigidity, but changes to lipid composition can simultaneously alter membrane thickness, spontaneous curvature, and leaflet symmetry, thus far preventing a systematic characterization of lipid composition on such curvature sensing through either experiment or simulation. Here we develop and apply a bilayer continuum membrane model that can tractably address this gap, quantifying how controlled changes to each material property can favor or disfavor protein curvature sensing. We evaluate both energetic and structural changes to vesicles upon helix insertion, with strong agreement to new experiments and all-atom MD simulations, respectively. Our membrane model builds on previous work to include both monolayers of the bilayer via representation by continuous triangular meshes. We introduce a coupling energy that captures the incompressibility of the membrane and the established energetics of lipid tilt. In agreement with experiment, our model predicts stronger curvature sensing in membranes with distinct tail groups (POPC vs DOPC vs DLPC), despite having identical head-group chemistry; the model shows that the primary driving force for weaker curvature sensing in DLPC is that it is thinner, and more wedge shaped. Somewhat surprisingly, asymmetry in lipid shape composition between the two leaflets has a negligible contribution to membrane mechanics following insertion. Our multi-scale approach can be used to quantitatively and efficiently predict how changes to membrane composition in flat to highly curved surfaces alter membrane energetics driven by proteins, a mechanism that helps proteins target membranes at the correct time and place.
细胞质蛋白必须募集到膜上才能在内吞作用和细胞分裂等过程中发挥作用。许多这类蛋白不仅能识别膜脂的化学结构，还能识别表面的曲率，与曲率更高的表面结合更紧密，即“曲率感知”。已知两亲性螺旋的曲率感知会随膜弯曲刚度而变化，但脂质组成的改变会同时改变膜厚度、自发曲率和小叶对称性，因此，到目前为止，无论是通过实验还是模拟，都无法对这种曲率感知上的脂质组成进行系统表征。在此，我们开发并应用了一种双层连续膜模型，该模型可以有效地填补这一空白，量化每种材料特性的可控变化如何促进或不利于蛋白的曲率感知。我们评估了螺旋插入后囊泡的能量和结构变化，分别与新的实验结果和全原子分子动力学模拟结果高度吻合。我们的膜模型基于之前的工作，通过连续三角形网格表示法包含了双层的两个单层。我们引入了一种耦合能，它捕捉了膜的不可压缩性和已确定的脂质倾斜能量学。与实验结果一致，我们的模型预测，尽管具有相同的头部基团化学性质，但具有不同尾部基团（POPC与DOPC与DLPC）的膜中曲率感知更强；该模型表明，DLPC中曲率感知较弱的主要驱动力是它更薄且呈楔形。有点令人惊讶的是，插入后两个小叶之间脂质形状组成的不对称对膜力学的贡献可以忽略不计。我们的多尺度方法可用于定量且有效地预测从平面到高度弯曲表面的膜组成变化如何改变由蛋白质驱动的膜能量学，这是一种帮助蛋白质在正确的时间和地点靶向膜的机制。
