Computational analysis of phosphoinositide signaling

磷酸肌醇信号传导的计算分析

• 批准号: 7447814
• 负责人: DIANA MURRAY
• 金额: $ 27.36万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7447814
• 关键词: Accounting; Affect; Binding; Bioinformatics; C2 Domain; Calcium; Cell physiology; Characteristics; Charge; Chemotaxis; Complex; Computer Analysis; Computing Methodologies; DNA Sequence Rearrangement; Development; Docking; Electrostatics; Event; Exocytosis; Figs - dietary; Future; Goals; Homology Modeling; Lateral; Ligand Binding; Ligands; Lipids; Localized; Malignant Neoplasms; Maps; Mediating; Membrane; Membrane Protein Traffic; Membrane Proteins; Methods; Modeling; Molecular; Molecular Structure; Mutation; Phosphatidylinositols; Play; Predisposition; Procedures; Property; Proteins; Regulation; Research; Role; Sampling; Signal Transduction; Simulate; Solvents; Structure; Surface; Surface Properties; Synaptic Vesicles; System; Systems Biology; Work; cell growth regulation; computer framework; driving force; insight; interest; interfacial; membrane model; microbial; research study; small molecule; tool

DESCRIPTION (provided by applicant): Our long-term goal is to continue the development of computational methods to describe quantitatively, at the molecular level, the physical forces responsible for the formation of macromolecular protein/lipid complexes at membrane surfaces. These complexes function in a variety of cellular processes such as interfacial signal transduction. Our overall hypothesis for the current proposal is that electrostatics plays a general role in phosphoinositide signaling and is manifested through phosphoinositide-mediated membrane association and the lateral organization of proteins and lipids. The first Specific Aim is to predict the membrane-associated orientations of phosphoinositide-binding domains and to describe quantitatively the effect of bound ligand on the electrostatic properties of these domains. Describing how phosphoinositides change the electrostatic character of these domains is crucial to understanding how membrane association is regulated: We hypothesize that binding of the highly negatively charged phosphoinositide neutralizes basic groups in the ligand-binding pocket and reduces the energetic barrier to insertion of hydrophobic motifs into the membrane interface. The second Specific Aim is to predict how phosphoinositides affect the membrane- associated orientations of C2 domains and, thus, contribute to calcium-mediated cellular processes such as synaptic vesicle exocytosis. We hypothesize that these interactions are driven mainly by non-specific electrostatic forces. The third Specific Aim is to simulate the lateral interactions among proteins and phosphoinositides at membrane surfaces in order to characterize the multimeric structures that form upon their organization. Such complexes play key roles in intracellular calcium release and cellular chemotaxis. We hypothesize that localized regions of negative and positive potential at the membrane surface serve as basins of attraction for molecules with opposite electrostatic characteristics and that electrostatics is a major driving force in forming these complexes. Our calculations will provide experimentally testable hypotheses for the membrane association of phosphoinositide binding domains, for membrane-mediated interactions, and for the regulation of both. A full description of electrostatic interactions will pave the way for the future study of other important interactions. Mutations that affect membrane targeting are implicated in cancer and microbial susceptibility. Thus, this research will provide insight into both normal and aberrant functionality.

描述（由申请人提供）：我们的长期目标是继续开发计算方法，以在分子水平上进行定量描述，即负责在膜表面形成大分子蛋白/脂质复合物的物理力。这些复合物在多种细胞过程中起作用，例如界面信号转导。我们对当前建议的总体假设是，静电在磷酸肌醇信号传导中起着一般作用，并通过磷酸肌醇介导的膜缔合以及蛋白质和脂质的横向组织表现出来。第一个具体目的是预测磷酸肌醇结合结构域的膜相关方向，并定量描述结合配体对这些结构域静电性能的影响。描述磷酸肌醇如何改变这些结构域的静电特征对于了解膜关联的调节是至关重要的：我们假设，高度负电荷的磷酸辛酰胺的结合将配体结合口袋中的基本组中和基本组的结合将能量障碍物插入到膜上膜上的能量障碍中。第二个具体目的是预测磷酸肌醇如何影响C2结构域的膜相关取向，从而有助于钙介导的细胞过程，例如突触小囊泡胞吐作用。我们假设这些相互作用主要由非特异性静电力驱动。第三个具体目的是模拟蛋白质和磷酸肌醇之间在膜表面的横向相互作用，以表征其组织上形成的多聚体结构。这种复合物在细胞内钙释放和细胞趋化性中起关键作用。我们假设膜表面的负和正势的局部区域是具有相反静电特性的分子的吸引盆地，并且静电是形成这些复合物的主要驱动力。我们的计算将为磷酸肌醇结合结构域，膜介导的相互作用以及两者的调节提供实验测试的假设。静电相互作用的完整描述将为未来对其他重要相互作用的研究铺平道路。影响膜靶向的突变与癌症和微生物敏感性有关。因此，这项研究将洞悉正常和异常功能。