MECHANOSENSITIVITY OF CELL MEMBRANES: ROLE OF LIPID-PROTEIN INTERACTIONS

细胞膜的机械敏感性：脂质-蛋白质相互作用的作用

• 批准号: 8364317
• 负责人: MIRIANAS CHACHISVILIS
• 金额: $ 0.11万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8364317
• 关键词: Biomedical Research; Cell membrane; Computer Simulation; Coupled; Data; Detection; Diffusion; Elements; Endothelial Cells; Fluorescence Resonance Energy Transfer; Funding; Future; G-Protein-Coupled Receptors; GTP-Binding Proteins; Goals; Grant; High Performance Computing; Lateral; Link; Lipid Bilayers; Lipids; Mechanical Stress; Membrane; Membrane Proteins; Modeling; Molecular; Molecular Conformation; Molecular Models; National Center for Research Resources; Nature; Principal Investigator; Process; Property; Proteins; Research; Research Infrastructure; Resources; Role; Signal Pathway; Source; Testing; Time; United States National Institutes of Health; Validation; Visual; Work; abstracting; conformational conversion; cost; design; molecular dynamics; molecular modeling; parent grant; physical property; receptor; research study; response; sensor; simulation; tool

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Mechanosensitivity of Cell Membranes: Role of Lipid-Protein Interactions PI: Mirianas Chachisvilis Abstract The goal of this project is to perform simulations at molecular dynamics (MD) and ab initio levels to support NIH grant R01 HL86943-3 (Mechanosensitivity of Cell Membranes: Role of Lipid-Protein Interactions, PI: M. Chachisvilis) and NSF grant MCB 0721396 (The Role of Dipole Potential In Mechanosensing, PI: M. Chachisvilis). The central hypothesis is that the plasma membrane of endothelial cell acts as a mechanosensitive element; i.e. changes in physical properties of the membrane under mechanical stress can regulate activity of membrane proteins coupled to intracellular signaling pathways. Due to rather basic nature of the specific aims of the parent grants, computational modeling would enable to link experimentally observed correlations between mechanically induced changes in the properties of lipid bilayer membrane and conformational changes in the receptor conformation using mechanistic molecular models. Computational modeling at the MD level will be used to model changes in lateral diffusion of lipid probes and conformational response of the G protein coupled receptor (GPCR) to specific changes in the lipid bilayer properties thereby enabling to confirm existence of the causative relationship between the conformational response and changes in bilayer properties under mechanical stress. Such theoretical confirmation would enable to draw more definite conclusions about the role of the plasma membrane in mechanosensing. Modeling capability will also enable to guide experimental work in designing and optimizing new FRET sensors for detection of GPCR and G protein activity which will significantly accelerate experimental work by enabling us to exclude from experimental construction unoptimal sensor configurations. Validation of the MD simulations by comparison with our experimental data will enable faster research progress in the future as it can eliminate the need for some expensive and time consuming experiments; validation of computational approach will also offer an efficient tool that can be used to test mechansosensitivity of many other potential mechanosensors during future research at the LJBI. More generally computational simulations will help to better understand processes underlying mechanochemical response by providing a visual representation of molecular geometries, spatial alignments and energetics that contribute to experimentally observed mechanosensitive conformational transitions.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， NCRR赠款不直接向子项目或子项目工作人员提供资金。 细胞膜的机械敏感性：脂质-蛋白质相互作用的作用PI：Mirianas Chachisvilis摘要本项目的目标是在分子动力学（MD）和从头算水平上进行模拟，以支持NIH资助R 01 HL 86943 -3（细胞膜的机械敏感性：脂质-蛋白质相互作用的作用，PI：M。Chachisvilis）和NSF授予MCB 0721396（机械感测中偶极电位的作用，PI：M. Chachisvilis）。中心假设是内皮细胞的质膜充当机械敏感元件;即在机械应力下膜的物理性质的变化可以调节与细胞内信号传导途径偶联的膜蛋白的活性。由于相当基本的性质的具体目标的父母赠款金，计算建模将能够链接实验观察到的相关性之间的机械诱导的脂质双层膜的性质的变化和构象变化的受体构象使用机械分子模型。MD水平的计算建模将用于模拟脂质探针的侧向扩散变化和G蛋白偶联受体（GPCR）对脂质双层特性特定变化的构象响应，从而能够确认机械应力下双层特性变化与构象响应之间存在因果关系。这样的理论确认将能够得出更明确的结论质膜在机械传感的作用。建模能力也将能够指导设计和优化用于检测GPCR和G蛋白活性的新FRET传感器的实验工作，这将通过使我们能够从实验构建中排除非最佳传感器配置来显着加速实验工作。通过与我们的实验数据进行比较来验证MD模拟将使未来的研究进展更快，因为它可以消除对一些昂贵和耗时的实验的需要;验证计算方法也将提供一个有效的工具，可用于在LJBI未来的研究中测试许多其他潜在的mechanosensitivity。更一般的计算模拟将有助于更好地了解过程的机械化学反应，通过提供一个直观的表示分子的几何形状，空间排列和能量，有助于实验观察到的机械敏感的构象转变。