Maingi Vishal, Rothemund Paul W K
Department of Bioengineering, California Institute of Technology, Pasadena, California 91125, United States.
Departments of Bioengineering, Computing + Mathematical Sciences, and Computation & Neural Systems, California Institute of Technology, Pasadena, California 91125, United States.
ACS Nano. 2021 Jan 26;15(1):751-764. doi: 10.1021/acsnano.0c07128. Epub 2020 Dec 21.
The properties of natural lipid bilayers are vital to the regulation of many membrane proteins. Scaffolded nanodiscs provide an lipid bilayer platform to host membrane proteins in an environment that approximates native lipid bilayers. However, the properties of scaffold-enclosed bilayers may depart significantly from those of bulk cellular membranes. Therefore, to improve the usefulness of nanodiscs it is essential to understand the properties of lipids restricted by scaffolds. We used computational molecular dynamics and modeling approaches to understand the effects of nanodisc size, scaffold type (DNA or protein), and hydrophobic modification of DNA scaffolds on bilayer stability and degree to which the properties of enclosed bilayers approximate bulk bilayers. With respect to achieving bulk bilayer behavior, we found that charge neutralization of DNA scaffolds was more important than the total hydrophobic content of their modifications: bilayer properties were better for scaffolds having a large number of short alkyl chains than those having fewer long alkyl chains. Further, complete charge neutralization of DNA scaffolds enabled better lipid binding, and more stable bilayers, as shown by steered molecular dynamics simulations that measured the force required to dislodge scaffolds from lipid bilayer patches. Considered together, our simulations provide a guide to the design of DNA-scaffolded nanodiscs suitable for studying membrane proteins.
天然脂质双层的特性对于许多膜蛋白的调节至关重要。支架化纳米盘提供了一个脂质双层平台，可在接近天然脂质双层的环境中容纳膜蛋白。然而，支架包围的双层的特性可能与大量细胞膜的特性有显著差异。因此，为了提高纳米盘的实用性，了解受支架限制的脂质的特性至关重要。我们使用计算分子动力学和建模方法来了解纳米盘大小、支架类型（DNA或蛋白质）以及DNA支架的疏水修饰对双层稳定性以及封闭双层特性接近大量双层程度的影响。关于实现大量双层行为，我们发现DNA支架的电荷中和比其修饰的总疏水含量更重要：对于具有大量短烷基链的支架，双层特性优于具有较少长烷基链的支架。此外，DNA支架的完全电荷中和能够实现更好的脂质结合以及更稳定的双层，这通过测定从脂质双层斑块中移除支架所需力的定向分子动力学模拟得到了证明。综合考虑，我们的模拟为设计适合研究膜蛋白的DNA支架化纳米盘提供了指导。
