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 Stebe智力优势：与脂质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产生的变形介导的。蛋白质通过插入脂质双层或通过粘附与膜结合来产生这些扭曲或包含物。然后蛋白质在脂质双层中自由横向移动，由储存在膜变形中的能量推动。类似地，纳米颗粒可以附着或插入膜中，产生随着与颗粒的距离而衰减的内含物。PI将研究具有复杂地形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/颗粒被等同地视为改变膜的局部形状的实体。夹杂物通过弯曲和拉紧膜产生多余的能量。当相邻变形场重叠时，膜的能量取决于制品/蛋白质取向和距离。此外，当孤立的夹杂物出现在具有复杂形貌的膜上时，夹杂物迁移到优选位置。这些相互作用发生在与膜张力和弯曲刚度相关的特征长度上，该特征长度通常在10- 100 nm之间。颗粒/蛋白质的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，这些相互作用尚未超出点扰动的水平。因此，优选的取向，排斥，和吸引力还没有被探索为夹杂物形状的函数。利用内含物几何学、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，产生具有特征主半径的内含物。这些内含物充当曲率传感器，并将迁移到平衡位置，在该位置，它们的固有曲率半径与宿主膜的曲率半径最佳匹配。因此，具有板状结构的蛋白质偏好相对平坦的位置，杆状结构偏好系链，弯曲板偏好类似曲率的位置，并且鞍状形状偏好膜颈。虽然这一一般概念越来越受到重视，但迄今为止，分析仅在假设线性叠加的弱变形极限下处理了弱非圆形夹杂物。研究人员建议研究各向异性夹杂物，以了解它们向首选曲率的位置的迁移和取向，以及它们的配对相互作用，作为膜张力和刚度的函数。他们将使用基于Helfrich模型中膜自由能的中尺度描述的分析和模拟来预测具有相关过量曲率和面积的正则形状夹杂物的蛋白质/膜相互作用。确定性的相互作用将使用分析和模拟的Helfrich模型，包括膜弯曲和张力进行研究。非确定性的相互作用将通过在共同PI Radhakrishnan开发的Helfrich Monte Carlo（MC）模型中考虑熵相互作用来模拟。虽然他们专注于中尺度相互作用，但他们将把这项工作与Radhakrishan小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膜上的颗粒/蛋白质建立规则。具有给定纵横比和弯曲的夹杂物如何在膜内相互作用。如何对相互作用规范，高度各向异性夹杂物形状将使用模拟和分析进行研究。他们的合作者Tobias Baumgart教授将在实验中检查预测。更广泛的影响科学/技术：这项工作将提供预测，以指导蛋白质/粒子在膜中的组装。在生物膜或颗粒或蛋白质的仿生系统内的各向异性组装具有未开发的前景，以设计新的定向组装，影响囊泡形成和出芽事件，促进治疗或纳米颗粒造影剂的摄取，并在感染期间深入了解病毒与宿主细胞的对接。指导女性和代表性不足的学生：欢迎来自外展倡议的学生参与与本研究相关的小型研究项目。(PI的个人联系人，项目种子，REU计划）。Stebe经常在关于工程领域的妇女和少数民族的论坛上发言，并在指导高中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代表性不足的群体。 (AWE在宾夕法尼亚大学和外部场馆）。Radhakrishnan学生参与：博士后指导：博士后职业发展是Stebe和Radhakrishnan小组的优先事项。