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: 8171933
• 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: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8171933
• 关键词: Cell membrane; Computer Retrieval of Information on Scientific Projects Database; Computer Simulation; Coupled; Data; Detection; Diffusion; Elements; Endothelial Cells; Fluorescence Resonance Energy Transfer; Funding; Future; G-Protein-Coupled Receptors; GTP-Binding Proteins; Goals; Grant; Institution; Lateral; Link; Lipid Bilayers; Lipids; Mechanical Stress; Membrane; Membrane Proteins; Modeling; Molecular; Molecular Conformation; Molecular Models; Nature; Process; Property; Proteins; Research; Research Personnel; Resources; Role; Signal Pathway; Source; Testing; Time; United States National Institutes of Health; Validation; Visual; Work; abstracting; conformational conversion; 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. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 细胞膜的机械敏感性：脂-蛋白相互作用的作用PI：Mirianas Chachisvilis摘要这个项目的目标是在分子动力学(MD)和从头计算水平上进行模拟，以支持美国国立卫生研究院授予R01HL86943-3(细胞膜的机械敏感性：脂质-蛋白质相互作用的作用，PI：M.Chachisvilis)和国家科学基金会授予MCB 0721396(偶极势能在机械传感中的作用，PI：M.Chachisvilis)。核心假设是内皮细胞的质膜作为机械敏感元件，即在机械应力作用下，膜的物理性质的变化可以调节与细胞内信号通路耦合的膜蛋白的活性。由于母体赠款的特定目标具有相当基本的性质，计算建模将能够使用机械分子模型将实验观察到的脂双层膜性质变化与受体构象变化之间的相关性联系起来。分子动力学水平上的计算模拟将被用来模拟脂质探针的侧向扩散的变化和G蛋白偶联受体(GPCR)对脂双层性质特定变化的构象反应，从而能够确认机械应力下构象反应和双层性质变化之间的因果关系的存在。这种理论上的证实将使人们能够对质膜在机械传感中的作用得出更明确的结论。建模能力还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，这将使我们能够从实验构建中排除不最佳的传感器配置，从而显着加快实验工作。通过与我们的实验数据比较验证MD模拟将使未来的研究进展更快，因为它可以消除一些昂贵和耗时的实验的需要；计算方法的验证还将提供一个有效的工具，可用于在LJBI未来的研究期间测试许多其他潜在机械传感器的机械灵敏度。更广泛地说，计算模拟将通过提供对分子几何、空间排列和能量的直观表示来帮助更好地理解机械力化学反应的潜在过程，这些分子几何、空间排列和能量有助于实验观察到的机械力敏感构象转变。