ELECTROSTATIC MODELING OF ION PORES

离子孔的静电建模

• 批准号: 3275886
• 负责人: Peter C Jordan
• 金额: $ 9.45万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1981
• 资助国家: 美国
• 起止时间: 1981-01-01 至 1995-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3275886
• 关键词: electrophysiology; mathematical model; membrane channels; membrane permeability; membrane potentials; membrane proteins; molecular dynamics; neurophysiology

The long range objective of this work is to use theoretical methods to relate the structure to the function of ion channel proteins. In particular, this proposal outlines some problems in neurophysiology. Electrostatic model calculations and molecular dynamics simulations descriptive of the process of ion permeation through transmembrane channel proteins are discussed. One set of electrostatic model calculations, based upon strictly continuum models, provides ways of determining how the shape of the channel protein, the location and density of charged groups, the composition of the electrolyte and the composition of the lipid affect the electrostatic energy profile governing ion access to and translocation through a channel and the electric field generated by transmembrane potentials. Another approach, by incorporating a simplified molecular treatment of the ion(s), water molecules and protein charges that surround and form the aqueous pore, is designed to rigorously account for molecular aspects of pore electrostatics. While continuing to treat the lipid and bulk water as continua it does not assume that pore water is continuum dielectric; instead, it derives the dielectric properties of pore water and provides an unambiguous way to establish the physical basis for ion channels' low electrostatic energy barriers. The molecular dynamics calculations, using a gramicidinlike channel as a model system, focus on some questions central to channel selectivity: the role of vestibule and binding site structure; the process of sequential resolvation during ion translocation; features promoting multiple occupancy. A proposed calculation modeling proton transport in a gramicidinlike channel may provide insights into the mechanism of proton translocation in protein systems generally. GRANt=R01AR28420 The work proposed in this grant application will extend our knowledge regarding the regulatory aspects of the bone forming cell, the osteoblast. The main thrust of this work is the description of a new role for type 5 tartrate resistant acid phosphatase (TRAP). This enzyme is present in osteoclasts and at sites of resorption and it is our hypothesis that the molecule has growth factor-like effects on bone cells. In preliminary findings we have shown that a molecule which is homologous to osteoclastic TRAP can stimulate isolated progenitor osteoblasts to acquire a more differentiated phenotype. The significance of such an effect is that TRAP, due to its location on the resorbing surface, can act as a site-specific molecule to direct the formation of bone to resorption lacunae. Thus, along with other soluble regulatory factors released during osteoclastic activity, TRAP may participate in local bone remodeling. In the first part if this project we intend 1) to characterize the effects of TRAP on bone cells and other cells, 2) to investigate whether known growth factors interact with it, and 3) to determine if it affects the production of TGF beta and bFGF. The second part of the project involves isolating and identifying the TRAP receptor and using the receptor to further characterize regulatory molecules in bone. (We currently believe that the receptor through which TRAP mediates its effects is the IGF- II/mannose-6- phosphate receptor, but this needs to be proven.) The last part of the project explores second messenger signalling mechanisms for TRAP and the possible role of intracellular calcium as a transducing agent. The importance of this work is that it may, for the first time, shed light on the localized nature of the bone remodelling process. Our central hypothesis is that the large amount of osteoclastic TRAP which remains on the surface of resorption lacunae can act as a site-directing regulatory molecule for the formation of new bone. These findings may also explain the high rates of osteoblastic activity in pathological states with high acid phosphates content, such as prostate metastases to the skeleton.

这项工作的远距离目标是使用理论方法 将结构与离子通道蛋白的功能相关联。 在 特别是，该建议概述了神经生理学中的一些问题。 静电模型计算和分子动力学模拟 通过跨膜通道的离子渗透过程描述 讨论蛋白质。 一组基于严格连续性的静电模型计算 模型提供了确定通道蛋白形状的方式， 带电组的位置和密度，组成 电解质和脂质的组成会影响静电 能源轮廓管理离子访问并通过通道易位 以及跨膜电位产生的电场。 另一种方法，通过合并简化的分子处理 离子（S），水分子和蛋白质电荷，围绕并形成 水孔被设计为严格说明分子方面 孔静电。 同时继续将脂质和大量水当作 连续性不认为孔隙水是连续的介电； 相反，它得出了孔隙水的介电特性，并提供了 明确的方法来建立离子频道低的物理基础 静电屏障。 分子动力学计算，使用gramicidinike通道作为一个 模型系统，专注于渠道选择性中心的一些问题： 前庭和结合位点结构的作用；顺序的过程 离子易位期间的分解；促进倍数的功能 占用。 提出的计算模拟质子在A中的转运 Gramicidinike通道可能会提供有关质子机制的见解 蛋白质系统中的易位。 格兰特= R01AR28420 本赠款申请中提出的工作将扩大我们的知识 关于骨形成细胞的调节方面，成骨细胞。 这项工作的主要目的是描述类型5的新角色 防strate抗酸性磷酸酶（陷阱）。 该酶存在于 破骨细胞和吸收部位，我们的假设是 分子对骨细胞具有类似生长因子的作用。 在初步 发现我们已经表明，与破骨碎屑同源的分子 陷阱可以刺激孤立的祖细胞成骨细胞以获取更多 分化的表型。 这种影响的意义在于陷阱， 由于其位置在吸收表面上，可以作为特定地点的 分子指导骨形成吸收空隙。 因此， 以及在破骨碎屑期间释放的其他可溶性调节因子 活动，陷阱可能参与局部骨骼重塑。 在第一部分中，如果我们打算1）表征效果 骨细胞和其他细胞上的陷阱，2）研究是否已知 生长因子与之相互作用，3）确定它是否影响 TGF Beta和BFGF的生产。 项目的第二部分涉及 隔离和识别陷阱受体并使用受体到 进一步表征骨骼中的调节分子。 （我们目前相信 诱捕介导其作用的受体是IGF- II/6-磷酸甘露磷酸盐受体，但这需要得到证明。）最后一个 该项目的一部分探讨了第二质信使信号传导机制 陷阱和细胞内钙作为转导剂的可能作用。 这项工作的重要性是，它可能首次发光 关于骨骼重塑过程的局部性质。 我们的中心 假设是保留在上面的大量破骨陷阱 吸收空隙的表面可以充当站点指导的调节 形成新骨的分子。 这些发现也可能解释 在高的病理状态中，成骨细胞活性的高率 酸性磷酸盐含量，例如前列腺转移到骨骼。