Particle/Protein Interaction and Migration via Anisotropic Membrane Deformation

通过各向异性膜变形实现颗粒/蛋白质相互作用和迁移

• 批准号: 1133267
• 负责人: Kathleen Stebe
• 金额: $ 20万
• 依托单位: University of Pennsylvania
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1133267&HistoricalAwards=false
• 关键词: Particle; Protein; Interaction; Migration; via

1133267StebeIntellectual Merit: Proteins associated with lipid membranes interact, migrate and assemble. One mode of interaction is mediated by deformations created by proteins in the membrane. Proteins create these distortions or inclusions by insertion in lipid bilayers or by association with the membrane by adhesion. The proteins are then free to move laterally in the lipid bilayers, propelled by energy stored in the membrane deformation. Similarly, nanoparticles can attach to or insert in membranes, creating inclusions that decay with distance from the particle. The PIs will study interactions between anisotropic inclusions on membranes with complex topography. On this level, proteins/ particles are treated equivalently as entities that change the local shape of the membrane. The inclusions create excess energy by bending and straining the membrane. When neighboring deformation fields overlap, the energy of the membrane depends on article/protein orientation and distance. In addition, when isolated inclusions occur on membranes with complex topography, the inclusions migrate to preferred locations. These interactions occur over a characteristic length related to the membrane tension and bending rigidity that is typically between 10-100nm. Particle/protein shape and energy anisotropy should play a key role in these interactions that has not been addressed beyond the level of point disturbances. Thus, preferred orientations, repulsions, and attractions have not been explored as a function of inclusion shape. Harnessing the interplay of inclusion geometry, interaction, and orientation would provide a powerful assembly tool.The motivating idea in the current literature is that proteins of different shapes are curvature inducers, creating inclusions with characteristic principle radii. These inclusions act as curvature sensors, and will migrate to the equilibrium position at which their intrinsic radii of curvature match optimally those of the host membrane. Thus, proteins with plate like structures prefer relatively planar locations,rod-like structures prefer tethers, bent plates prefer locations of like curvature, and saddle-like shapes prefer membrane necks. While this general concept is gaining traction, analyses have thus far addressed only weakly non-circular inclusions in the limit of weak deformations assuming linear superposition. The researchers propose to study anisotropic inclusions to understand their migration and orientation to sites of preferred curvature, and their pair interactions, as a function of membrane tension and rigidity. They will use analysis and simulation based on a mesoscale description of the membrane free energy in terms of a Helfrich model to predict protein/membrane interactions for canonically shaped inclusions with associated excess curvatures and areas. Deterministic interactions will be studied using analysis and simulation in terms of the Helfrich model including membrane bending and tension. Non-deterministic interactions will be simulated by accounting for entropic interactions in a Helfrich Monte Carlo (MC) model developed by the co-PI Radhakrishnan. While they focus on mesoscale interactions, they will relate the work to the ongoing molecular-scale simulations of protein-membrane interactions in the Radhakrishan group. Their aim is to establish rules for particles/proteins on curved and stretched membranes. How does an inclusion with a given aspect ratio and bending interact within the membrane. How do pairs interact Canonical, highly anisotropic inclusion shapes will be studied using simulation and analysis. Their collaborator, Prof. Tobias Baumgart, will check predictions in experiment.Broader Impacts Scientific/ Technological: This work will provide predictions to direct assembly of proteins/particles in membranes. Anisotropic assembly within biomembranes or biomimetic systems of particles or proteins hold untapped promise to engineer new oriented assemblies, to influence vesiculation and budding events, to promote uptake of therapeutic or nanoparticle contrast agents, and to gain insight into viral docking to host cells during an infection. Mentoring of Female and Under-represented Students: Students from outreach initiatives will be welcome to work on small research projects associated with this research. (PI's personal contacts, Project SEED, REU programs). Stebe regularly speaks in forums concerning women and minorities in engineering and has extensive experience in directing research experiences for highschool and undergraduate students, often femake or from under-represented groups. (AWE at Penn, and external venues). Radhakrishnan Student Participation: Postdoctoral mentoring: Postdoctoral career development is a priority in the Stebe and Radhakrishnan groups.

1133267 StebeIntelligence优点：与脂膜相关的蛋白质相互作用、迁移和组装。一种相互作用模式是由膜中蛋白质造成的变形所介导的。蛋白质通过插入脂类双层或通过黏附与膜结合而产生这些扭曲或包涵体。然后，在膜变形中储存的能量的推动下，蛋白质可以在脂质双层中自由横向移动。同样，纳米颗粒可以附着在膜上或插入膜中，产生的包裹体会随着距离颗粒的距离而衰减。PI将研究具有复杂形貌的膜上各向异性夹杂物之间的相互作用。在这个层面上，蛋白质/颗粒被同等地视为改变膜局部形状的实体。夹杂物通过弯曲和拉紧薄膜来产生多余的能量。当相邻的变形场重叠时，膜的能量取决于物品/蛋白质的取向和距离。此外，当孤立夹杂物出现在具有复杂形貌的膜上时，夹杂物会迁移到首选位置。这些相互作用发生在与膜张力和弯曲刚性相关的特征长度上，通常在10-100 nm之间。粒子/蛋白质形状和能量各向异性应该在这些相互作用中发挥关键作用，这些作用还没有超出点干扰的水平。因此，作为包裹体形状的函数，优选取向、排斥力和吸引力还没有被探索。利用包涵体几何结构、相互作用和取向的相互作用将提供一个强大的组装工具。当前文献中的激励思想是不同形状的蛋白质是曲率诱导剂，产生具有特征原理半径的包裹体。这些包裹体充当曲率传感器，并将迁移到其固有曲率半径与宿主膜的曲率半径最佳匹配的平衡位置。因此，具有板状结构的蛋白质更喜欢相对平面的位置，杆状结构更喜欢系链，弯曲的板状更喜欢类似曲率的位置，而鞍状形状更喜欢膜颈部。虽然这一一般概念正在获得吸引力，但到目前为止，分析仅讨论了假设线性叠加的弱变形极限中的弱非圆形包裹体。研究人员建议研究各向异性包裹体，以了解它们作为膜张力和刚性的函数向优先曲率位置的迁移和取向，以及它们之间的相互作用。他们将根据Helfrich模型对膜自由能的介观描述进行分析和模拟，以预测具有相关超额曲率和面积的正则形状包裹体的蛋白质/膜相互作用。确定性的相互作用将根据Helfrich模型进行分析和模拟，包括薄膜弯曲和拉伸。非确定性相互作用将在由合作者Pi Radhakrishnan发展的Helfrich蒙特卡罗(MC)模型中考虑熵相互作用来模拟。虽然他们专注于中尺度的相互作用，但他们将把这项工作与RadhakrMountain组正在进行的蛋白质-膜相互作用的分子尺度模拟联系起来。他们的目标是为弯曲和拉伸的膜上的颗粒/蛋白质建立规则。具有给定长宽比和弯曲的夹杂物如何在膜内相互作用。我们将通过模拟和分析来研究金属对如何相互作用形成标准的、高度各向异性的夹杂物形状。他们的合作者Tobias Baumgart教授将在实验中检验预测。布罗德影响科学/技术：这项工作将为蛋白质/颗粒在膜中的直接组装提供预测。在生物膜或颗粒或蛋白质的仿生系统内的各向异性组装在设计新的定向组装、影响囊泡形成和萌发事件、促进治疗性或纳米颗粒造影剂的摄取以及洞察感染期间病毒与宿主细胞的对接方面具有尚未开发的前景。指导女性和代表性不足的学生：将欢迎来自外联倡议的学生参与与这项研究相关的小型研究项目。(PI的个人联系人、SEED计划、REU计划)。Stebe经常在关于工程领域女性和少数族裔的论坛上发言，他在指导高中生和本科生的研究经验方面拥有丰富的经验，这些学生通常是女性或来自代表性不足的群体。(在宾夕法尼亚大学和外部场馆的敬畏)。Radhakrishnan学生参与：博士后指导：在Stebe和Radhakrishnan小组中，博士后职业发展是优先事项。