MECHANOSENSITIVITY OF CELL MEMBRANES: ROLE OF LIPID-PROTEIN INTERACTIONS

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 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横向扩散的变化和G蛋白偶联受体（GPCR）对脂质双层性质特定变化的构象响应，从而能够确认构象响应之间存在因果关系和机械应力下双层性质的变化。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。

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.