Theory and Simulation of Membrane Deformations Orchestrated by Intracellular Molecular Assemblies

0853389 Radhakrishnan“该奖项是根据2009年美国复苏和再投资法案（公法111-5）资助的。“细胞膜和膜基细胞器积极介导几个细胞内信号传导和运输决定。越来越多的应用依赖于分子组装体和膜之间的协同相互作用。然而，基于膜和膜介导的信号传导的研究并不被认为是系统生物学的核心方面。虽然细胞膜介导的信号转导的连贯和完整的描述并不总是可能的实验方法，多尺度建模和模拟方法可以提供有价值的见解，在纳米/微观和介观尺度。本项目致力于开发一个理论和计算平台，用于定量描述细胞膜拓扑结构如何被细胞内蛋白质组装体主动介导和操纵。具体而言，该提案描述了一个综合研究和推广计划，涉及细胞内吞转运机制的多尺度建模研究，即，主动运输机制的特点是囊泡成核和蛋白质相互作用网络协调的细胞膜出芽。含时Ginzburg朗道的动力学Monte Carlo方法（KMC-TDGL）算法在PI以前的研究计划下开发，代表了方法论的进步，因为它独特和创新的能力，联合收割机两个不同的现象学形式主义（动力学Monte Carlo和时间依赖的Ginzburg朗道），以获得在低膜曲率下曲率诱导蛋白如何介导细胞膜变形的统一图像。在这个项目中，将开发两种新的模拟方法，可以预测蛋白质诱导的膜变形在高曲率极限。在目标1中，将开发表面进化方法来预测高度弯曲的轴对称膜结构的最小能量构象，该结构与通过网格蛋白介导的内吞作用过程的细胞表面受体的内化有关。在目标2中，将开发一种新的方法，称为本地坐标TDGL，以扩大目标1的结果，通过计算有限的温度性能的任意（没有强加的对称性）弯曲的膜，包括系统的自由能。在目标3中，将探索控制网格蛋白介导的内吞作用的定量生物能量学的特定生物学假设。拟议的模拟框架将使分子驱动力和新兴功能的内吞贩运/运输网络之间的定量联系的发展。拟议的模拟也将提供严格的基础上，由于同源受体或受体突变，这往往获得突出功能失调的贩运pathways.Broader影响的分子相互作用的基础上区分细胞内的贩运命运的理论和建模方法，预计将创造许多新的应用在系统生物学，药理学和纳米生物技术的途径。这里探讨的内吞作用的具体应用将提供一个直接的途径来辨别病理细胞贩运的命运牵连在各种生物医学条件，如癌症和精神分裂症。作为跨学科研究计划的补充，教育和推广计划由工程和生物学本科生的严格和有远见的研究培训构成。为了实现更广泛的影响，在补充本科生的研究经验，三维立体环境可视化生物分子结构和动画建立和利用分子建模和模拟技术在本科生和研究生的指令。

0853389Radhakrishnan"This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5)."Cell membranes and membrane based organelles actively mediate several intracellular signaling and trafficking decisions. A growing number of applications rely on cooperative interactions between molecular assemblies and membranes. Yet, the studies of membrane based and membrane mediated signaling are not considered core aspects of systems biology. While a coherent and complete description of cell membrane mediated signaling is not always possible by experimental methods, multiscale modeling and simulation approaches can provide valuable insights at nano/microscopic and mesoscopic scales. This project strives to develop a theoretical and computational platform for quantitatively describing how cell membrane topologies are actively mediated and manipulated by intracellular protein assemblies. Specifically, the proposal describes an integrated research and outreach program, involving a multiscale modeling study of Intracellular Endocytotic trafficking mechanisms, i.e., active transport mechanisms characterized by vesicle nucleation and budding of the cell membrane orchestrated by protein interaction networks.Intellectual Merit: The kinetic Monte Carlo time dependent Ginzburg Landau (KMC-TDGL) algorithm developed under the PIs previous research program represents a methodological advance because of its unique and innovative in its ability to combine two disparate phenomenological formalisms (Kinetic Monte Carlo and Time Dependent Ginzburg Landau) in order to obtain a unified picture of how curvature inducing proteins mediate cell membrane deformations under low membrane curvature. In this project, two new simulation approaches will be developed, which can predict protein induced membrane deformations in the high curvature limit. In Aim 1, the surface evolution method will be developed to predict minimum energy conformations of highly curved axis symmetric membrane structures relevant to the internalization of cell surface receptors through the process of clathrin mediated endocytosis. In Aim 2, a new method referred to as the local coordinate TDGL will be developed in order to extend the results of Aim 1 by computing finite temperature properties of arbitrarily (no imposed symmetry) curved membranes including the free energies of the system. In Aim 3, specific biological hypothesis governing the quantitative bioenergetics of clathrin mediated endocytosis will be explored. The proposed simulation framework will enable the development of a quantitative link between molecular driving forces and emergent functionality in endocytotic trafficking/transport networks. The proposed simulations will also provide rigorous foundations for differentiating intracellular trafficking fates on the basis of differences in molecular interactions due to homologous receptors or receptor mutations, which often gain prominence in dysfunctional trafficking pathways.Broader Impact: The proposed theory and modeling approaches are expected to create avenues for many novel applications in systems biology, pharmacology, and nanobiotechnology. The particular application to endocytosis explored here will provide a direct route to discern pathological cellular trafficking fates implicated in a variety of biomedical conditions such as cancer and schizophrenia. Complementing the interdisciplinary research program, the educational and outreach programs are constituted by rigorous and visionary research training for undergraduate students in engineering and biology. To achieve broader impact in complementing the undergraduate research experience, a three dimensional stereo environment for visualizing biomolecular structure and animations is established and utilized for the instruction of molecular modeling and simulation techniques at the undergraduate and graduate students.