Computational analysis of phosphoinositide signaling

磷酸肌醇信号传导的计算分析

• 批准号: 7430239
• 负责人: DIANA MURRAY
• 金额: $ 6.77万
• 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/7430239
• 关键词: binding sites; bioinformatics; biological signal transduction; calcium flux; chemical binding; chemical group; chemical models; computational biology; computer simulation; intermolecular interaction; ionic bond; lipid bilayer membrane; macromolecule; mathematical model; membrane activity; membrane model; membrane potentials; membrane proteins; model design /development; phosphatidylinositols; statistics /biometry

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，以在分子水平上定量描述负责在膜表面形成大分子蛋白质/脂质复合物的物理力。这些复合物在多种细胞过程中发挥作用，例如界面信号转导。我们对当前提议的总体假设是，静电在磷酸肌醇信号传导中发挥一般作用，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来体现。第一个具体目标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质的影响。描述磷酸肌醇如何改变这些结构域的静电特性对于理解如何调节膜缔合至关重要：我们假设带高负电荷的磷酸肌醇的结合中和了配体结合袋中的碱性基团，并减少了疏水基序插入到其中的能量障碍。膜界面。第二个具体目标是预测磷酸肌醇如何影响 C2 结构域的膜相关方向，从而促进钙介导的细胞过程，例如突触小泡胞吐作用。我们假设这些相互作用主要由非特异性静电力驱动。第三个具体目标是模拟膜表面蛋白质和磷酸肌醇之间的横向相互作用，以表征在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发挥关键作用。我们假设膜表面的负电势和正电势的局部区域充当具有相反静电特性的分子的吸引盆，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域的膜关联、膜介导的相互作用以及两者的调节提供可通过实验检验的假设。对静电相互作用的完整描述将为未来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易感性有关。因此，这项研究将提供对正常和异常功能的深入了解。