Using computer simulations to elucidate ion channel function

我们身体中数以万亿计的细胞必须相互通信。信息可以通过带电粒子、离子进出细胞所产生的微小电信号来传递。离子通过称为离子通道的造孔蛋白通过细胞膜。离子通道有多个亚基和许多运动部分，并对各种刺激做出反应而开放。目前，我们对离子通道功能的分子机制的了解存在很大差距，阻碍了对基本生理过程的深入了解。我的研究旨在填补两种离子通道的空白，这两种离子通道在我们的神经系统中发挥关键作用，例如，在疼痛感觉和认知功能中，或者在肌肉细胞中，例如，对稳定心律至关重要。控制这些离子通道功能的机制没有得到充分的研究。我们的短期目标是了解这些通道机制的具体细节，与激活和调节有关。这将提供基本的洞察力，我们可以在此基础上建立未来的项目。长期目标是获得这些离子通道在自然环境中如何工作的原子级别的描述，有助于详细了解离子通道的生理学。离子通道的打开和关闭；因此，动力学对于功能是必不可少的。实验方法可以确定离子通道的三维结构，提供离子通道的模型作为及时的快照。不幸的是，这些都是特定国家的静态图像。为了充分理解离子通道功能所涉及的分子机制，我们必须研究将这些态联系在一起的动力学。我的研究使用计算机模拟，它预测离子通道随时间的运动，说明结构的变化。原则上，这些模拟就像一个计算显微镜，使静态结构栩栩如生。我的研究生和本科生团队将使用动态模拟来研究一个离子通道的两种类型的激活和另一种通道的两种类型的调节。因此，我们将获得这些通道的激活和调节机制的第一个原子水平的描述。我们的研究是推动这一领域向前发展的核心，因为计算机模拟可以揭示其他方法无法揭示的细节。如果没有观察蛋白质动力学的能力，结构和功能研究之间就会出现鸿沟。模拟弥补了这一差距，因为结构为模拟提供了输入，可以解释功能实验。了解生理功能的分子细节可能会导致对病理生理学的洞察。因此，我们基础NSE研究的结果最终可以转移到最终用户手中，以改进对两个具有巨大未开发药物潜力的离子通道的药物发现。这将通过改进治疗疼痛、中风和壁炉心律失常的药物的设计，使加拿大制药业和加拿大人民受益。

The trillions of cells in our body must communicate with each other. Information can be conveyed through small electrical signals generated by the movement of charged particles, ions, into and out of cells. Ions pass the cell membrane through pore-forming proteins called ion channels. Ion channels have multiple subunits and many moving parts, and open in response to a variety of stimuli. Currently, large gaps in our understanding of the molecular mechanisms underlying ion channel function impede insight into fundamental physiological processes. My research aims to fill these gaps for two types of ion channels that play crucial roles in our nervous system, e.g., in pain sensing and cognitive functions, or in muscle cells, e.g. critical for a stable heart rhythm. The mechanisms controlling the function of these ion channels are under-examined. Our short-term goal is to understand specific details in the mechanisms of these channels, relating to activation and regulation. This will provide fundamental insight on which we can build future projects. The long-term objective is to obtain an atomic-level description of how these ion channels work in a native environment, contributing to a detailed understanding of ion channel physiology. Ion channels open and close; therefore, dynamics are essential for function. Experimental methods can determine the three-dimensional structure, providing a model of the ion channel as a snapshot in time. Unfortunately, these are still images of particular states. To fully understand the molecular mechanisms involved in ion channel function, we must study the dynamics that tie the states together. My research uses computational simulations, which predict the motion of ion channels over time, illustrating changes in structure. In principle, these simulations work as a computational microscope and bring static structures to life. My team of graduate and undergraduate students will use dynamical simulations to study two types of activation for one ion channel and two types of regulation for another channel. Hence, we will obtain the first atomic-level description of activation and regulation mechanisms for these channels. Our research is central to driving the field forward as computer simulations can reveal details that other methods cannot. Without the ability to observe protein dynamics, a gap is left between structural and functional research. Simulations bridge this gap, as structures provide input for simulations that can explain functional experiments. Understanding molecular details of physiological function likely leads to pathophysiological insight. Hence, results from our fundamental NSE research can eventually be transferred to end users to improve drug discovery for two ion channels with large, unexploited pharmaceutical potential. This will benefit the Canadian pharmaceutical industry and Canadian population, through the design of improved drugs for treatment of, e.g., pain, stroke and hearth arrhythmias.