Theory and Simulation of Membrane Deformations Orchestrated by Intracellular Molecular Assemblies

“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。”细胞膜和基于膜的细胞器积极地介导细胞内的信号传导和运输决策。越来越多的应用依赖于分子组件和膜之间的合作相互作用。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。虽然通过实验方法对细胞膜介导的信号传导进行连贯和完整的描述并不总是可能的，但多尺度建模和模拟方法可以在纳米/微观和介观尺度上提供有价值的见解。该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是如何被细胞内蛋白质组装积极介导和操纵的。具体来说，该提案描述了一个综合研究和推广计划，涉及细胞内内吞运输机制的多尺度建模研究，即由蛋白质相互作用网络协调的以囊泡成核和细胞膜出芽为特征的主动运输机制。智力优势：动力学蒙特卡罗时间相关的金兹堡朗道（KMC-TDGL）算法在pi之前的研究计划下开发，代表了一种方法上的进步，因为它独特而创新地结合了两种不同的现象学形式（动力学蒙特卡罗和时间相关的金兹堡朗道），以获得曲率诱导蛋白质如何在低膜曲率下介导细胞膜变形的统一图像。在本项目中，将开发两种新的模拟方法，可以预测高曲率极限下蛋白质诱导的膜变形。在Aim 1中，将开发表面演化方法来预测通过网格蛋白介导的内吞作用过程中与细胞表面受体内化相关的高度弯曲轴对称膜结构的最小能量构象。在Aim 2中，将开发一种称为局部坐标TDGL的新方法，通过计算任意（无强加对称）弯曲膜的有限温度特性（包括系统的自由能）来扩展Aim 1的结果。在Aim 3中，将探讨控制网格蛋白介导的内吞作用定量生物能量学的特定生物学假设。所提出的模拟框架将能够在分子驱动力和内吞贩运/运输网络中的紧急功能之间建立定量联系。所提出的模拟还将为基于同源受体或受体突变引起的分子相互作用差异来区分细胞内运输命运提供严格的基础，这通常在功能失调的运输途径中得到突出体现。更广泛的影响：所提出的理论和建模方法有望为系统生物学、药理学和纳米生物技术的许多新应用创造途径。本文探讨的内吞作用的特殊应用将为辨别与各种生物医学疾病（如癌症和精神分裂症）有关的病理细胞运输命运提供直接途径。作为跨学科研究项目的补充，教育和推广项目由对工程和生物学本科生的严格和有远见的研究培训组成。为了实现更广泛的影响，以补充本科生的研究经验，建立了一个三维立体环境，用于可视化生物分子结构和动画，并用于指导本科生和研究生的分子建模和模拟技术。

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.