COMPUTATIONAL APPROACHES TO UNDERSTANDING ION CHANNEL GATING

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 膜转运体和通道负责将离子和分子从膜的一侧移动到另一侧。这一运动完成了一系列任务，从创建用于为细胞过程提供动力的离子梯度到产生通过中枢神经系统传播的电信号。目前的提案研究了与糖转运蛋白vSGLT和酸敏离子通道ASIC的操作相关的构象变化。这两种膜蛋白都会对环境中的信号做出反应，在功能上重要的状态之间切换。在vSGLT的情况下，它必须结合细胞外空间的钠离子和糖分子，然后经历构象变化，为分子进入细胞创造物理出口。ASIC对细胞外空间的pH值变化作出反应，导致它打开或关闭穿过分子的跨膜小孔，以允许钠离子进入细胞质。我们打算使用计算方法解决的两个突出问题是分子变化发生所需的较长时间以及这些膜蛋白与效应分子相互作用的选择性。我们完全期待这项提案中概述的工作将具体阐明vSGLT和ASIC的生物学，以及经历构象变化并与结合伙伴具体相互作用的一类非常大的蛋白质。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Membrane transporters and channels are responsible for moving ions and molecules from one side of the membrane to the other. This movement accomplishes a wide range of tasks from creating ionic gradients used to power cellular processes to generating electrical signals that propagate through the central nervous system. The current proposal examines the conformational changes associated with the operation of a sugar transporter, vSGLT, and the acid sensing ion channel, ASIC. Both of these membrane proteins respond to cues in the environment to switch between functionally important states. In the case of vSGLT, it must bind a sodium ion and a sugar molecule from the extracellular space and then undergo a conformational change to create a physical exit for the molecules into the cell. ASIC responds to changes in the pH of the extracellular space causing it to open or close a membrane-spanning pore through the molecule to permit the passage of sodium ions into the cytoplasm. Two outstanding questions that we intend to use computational methods to address are the long times required for molecular changes to occur and the selective nature with which these membrane proteins interact with effector molecules. We fully expect that the work outlined in this proposal will shed light specifically on the biology of vSGLT and ASIC as well as the very large class of proteins that undergo conformational changes and interact specifically with binding partners.