ELECTROSTATIC MODELING OF ION PORES

离子孔的静电建模

• 批准号: 6612813
• 负责人: Peter C Jordan
• 金额: $ 29.27万
• 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 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6612813
• 关键词: bioenergetics; dielectric property; intermolecular interaction; ionic bond; lipid bilayer membrane; mathematical model; membrane channels; membrane model; membrane permeability; membrane potentials; model design /development; molecular dynamics; nuclear magnetic resonance spectroscopy; physical model; water

This proposal describes theoretical ways to relate structural features of ion channel proteins and of their phospholipid environment to channel behavior, stressing problems central to excitable cell physiology. Model calculations clarifying issues in permeation and selectivity are described. An improved approach to simulation, constructing force fields reliable in channel environments, is described. A new way to treat lipid influences on channels is outlined. Calculations of free energy profiles, based on an exact, computationally efficient way to treat a limited number of molecular features of the ion(s), water and protein charges that surround and form the aqueous pore, are proposed and used to understand and interpret major structural features of the selectivity domain of potassium channels: Why is it multiply occupied? Why does it reject small alkali cations? Why is the bridge water loosely coordinated? The method is applied to crystalline gramicidin conformers to determine why some favor anion occupancy. As more channel structural data (on nicotinic receptor and voltage gated cation families) become available, their selectivity and permeation characteristics will be investigated. Ways to meld these exact techniques with standard simulational methods are described. An application that may disentangle the enthalpic from the entropic influences on the permeation kinetics of the model potassium channel is presented. A new way to construct water-water and ion-water force fields is outlined. This approach, by accurately treating short-range structural forces and intermediate range electrostatics, is designed to yield force fields reliable over a wide range of thermodynamic phase space. Water and hydrated species in channels and in bulk water are very different structurally. Reliable simulational methods must account for these differences. The new force fields, being valid over extended p-V-T domains, answer this need. Channel formation is greatly influenced by interaction with the membrane. The crucial interactions correlate surface displacements in membrane regions about a bilayer width apart. At such short separations elastic behavior becomes cooperative. A new electroelastic theory of membranes is outlined and used to study peptide insertion energetics.

该建议描述了将离子通道蛋白及其磷脂环境的结构特征与通道行为联系起来的理论方法，这强调了令人兴奋的细胞生理中心的问题。描述了阐明渗透和选择性问题的模型计算。描述了一种改进的模拟方法，即在通道环境中可靠的构建力场。概述了一种治疗脂质影响的新方法。提出并用于理解和解释含钾通道的选择性领域的主要结构特征，以基于确切的计算有效方法来处理有限数量的离子，水和蛋白质电荷的分子特征的有限分子特征，计算自由能曲线的计算：为什么要占用钾通道？为什么它拒绝小碱阳离子？为什么桥水松散地协调？该方法适用于晶粒蛋白构象体，以确定为什么有些人有利于阴离子占用率。随着越来越多的通道结构数据（关于烟碱受体和电压门控阳离子家族）的可用性，将研究它们的选择性和渗透特性。描述了与标准模拟方法融合这些精确技术的方法。提出了一种可能使焓影响模型钾通道渗透动力学的应用程序。概述了一种构建水水和离子水力场的新方法。通过准确处理短距离结构力和中间范围静电，这种方法旨在在各种热力学相空间中产生可靠的力场。在结构上，在通道和大量水中的水和水合物种在结构上非常不同。可靠的模拟方法必须解决这些差异。在扩展的P-V-T域上有效的新力场可以解决此需求。通道形成受到与膜相互作用的极大影响。关键的相互作用将膜区域的表面位移相关联，围绕双层宽度分开。在如此短暂的分离下，弹性行为变得合作。概述了一种新的膜电弹理论，并用于研究肽插入能量学。