磷脂膜融合过程中蛋白与膜相互作用的曲率相关性及其分子机制研究

Membrane fusion plays a crucial role in the process of neurotransmission, endocytosis and drug delivery. The fusion process is mainly regulated by fusion proteins and membrane, But how the protein interacts with membrane and how this interaction influences and regulates fusion process is still unclear. It has been verified by some researches that the interaction of two important proteins (complexin and alpha-synuclein) and membrane in the membrane fusion is a membrane curvature sensing process. But only experiment and coarse-grained simulation methods have been used in related researches, the atomic molecular dynamics and mechanisms cannot be reached by such research methods, the reason and mechanisms of membrane curvature sensing also cannot been well characterized and explained. In this study, all-atom molecular simulation will be used to study the mechanisms of membrane curvature sensing in protein-membrane interaction during membrane fusion, including: establish reasonable and accuracy all-atom protein and membrane models; calculate the molecular dynamics of protein-membrane interaction; quantify the structure and free energy changes within interaction process and related molecular mechanisms. This will promote the understanding of the molecular and regulation mechanisms of fusion process, it is also have an important significance for the understanding of the mechanisms in some basic physiological phenomenon such as neurotransmission.

磷脂膜融合是神经传导、胞吞胞吐、药物输运等过程中的一个关键环节。融合过程主要受蛋白以及磷脂膜的调控，但蛋白如何与磷脂膜产生相互作用进而影响和调控融合过程的分子机制仍有待进一步的探索与研究。研究表明，融合过程中两个重要蛋白（complexin和alpha-synuclein）和磷脂膜的相互作用与膜曲率有着密切的联系。但这些研究仅限于实验观察或粗粒化的分子动力学模拟，无法得到原子尺度下蛋白与磷脂膜相互作用曲率相关性的动力学过程，更无法解释这种曲率相关性的原因与分子机制。因此，本项目拟借助全原子分子动力学模拟方法来研究融合过程中蛋白与磷脂膜相互作用曲率相关性的分子机制，包括：建立合理准确的蛋白及磷脂膜全原子模型；模拟蛋白与有曲率磷脂膜相互作用的动力学过程；量化过程中结构及自由能变化和相关分子机制等。这将有助于更好地理解融合的过程和调控机理，对深入理解神经传导等基本生理现象的机制也有着重要的意义。

本项目围绕磷脂膜与蛋白间相互作用中的曲率相关性以及分子机制进行研究。研究发现磷脂膜与complexin C端以及alpha-synuclein N端的相互作用都具有曲率相关性，两种蛋白都优先与具有高曲率的磷脂膜产生结合。这种结合是由于曲率诱导在磷脂膜表面产生了大量的缺陷，使得疏水性氨基酸能够更容易插入磷脂膜内产生相互作用。磷脂膜表面的缺陷与磷脂膜的曲率成正比，并且会随着胆固醇含量的升高而增加，因此胆固醇能够增强磷脂膜与蛋白间的相互作用。此外，磷脂成分PE能够增强磷脂膜与蛋白间的氢键相互作用，从而增强磷脂膜与蛋白间的结合。

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