膜弯曲的产生机制及其对蛋白质吸附的影响

Cellular membrane is the platform for reactions of biomolecules, which supports and regulates the complex structures and functions of the cell. The physical properties of membrane, such as shape and tension, can affect the chemical behavior of the constituent molecules; meanwhile, the absorption and recruitment of the chemical composition can dynamically modulate the membrane physical shapes. The coupling and interplay between the individual biomolecules and the shaped membrane determine the biological properties of the cell. Understanding these interactions is essential to realize the function regulation of cellular membrane. In this project, we will develop efficient solvent-free Dissipative Particle Dynamics simulations for lipid bilayer and polypeptides. We will investigate the generation of spontaneous curvature and shapes of bilayers induced by absorption of proteins or polypeptides, and interpret the corresponding mechanism in molecular level. We will also study the absorption and sorting of amphiphilic peripheral peptides and protein motifs driven by spherical vesicles and membrane tubes with different curvatures, and analyze the underlying mechanism based on the changes of microscope structures. The accomplishment of this project will provide new insight into the function-related shapes of membrane, and assist drug designing and synthetic cell assembling.

细胞膜是生物分子反应的平台，支撑并调节细胞的复杂结构和功能。膜的形状、张力等物理性质会改变膜的组成分子的化学行为；而生物分子在膜上的吸附和聚集也会调节膜的结构等物理性质。膜的化学组分和其物理形状之间相互耦合、交互影响，决定了细胞的生物性质。深入理解这些作用有助于实现细胞膜功能调控。本项目将发展适用于磷脂双层膜和多肽的无水耗散粒子动力学模拟方法，实时动态研究蛋白或多肽吸附诱导的膜的自发曲率和形变，在分子层次解释膜形变的产生机制；研究具有双亲结构的外围多肽或蛋白模体在不同曲率的球形囊泡及膜管表面的吸附和聚集，从微观结构变化分析曲率对蛋白吸附和聚集影响的机制。本项目的完成将会加深对膜结构与功能关系的理解，进而辅助药物设计和组装人造细胞。

生物分子在细胞膜上的吸附和聚集会使细胞和细胞器具有复杂多变的形状，而膜的复杂弯曲结构并不是细胞活动的被动产物，它在膜的结构域形成和细胞输运方面起主动作用。本项目采用多尺度分子动力学模拟的方法系统研究了多种因素诱导的膜弯曲，对曲率变化进行了定量计算，并分析了多肽在弯曲膜上的吸附与聚集行为。首先我们发展了无水耗散粒子动力学力场，以保证能在细胞尺度模拟膜的结构变化；自主开发了多种分析程序，用于定量计算膜的结构和热力学性质。然后我们系统研究了多种类型的抗菌小肽、粘菌素、二价金属离子、以及天然无序蛋白诱导膜发生形变的机制，深入探究了各种分子的结构、亲疏水能力以及浓度对膜的有序度、弯曲刚度和曲率等性质的影响，归纳出定性和定量规律。我们还探究了膜的固有曲率对多肽和天然无序蛋白吸附和聚集的影响，分析了能量驱动和熵驱动的作用。本项目的部分研究成果已经用于指导抗菌药物的设计，也将有助于组装有特定功能的人造细胞。