Using computer simulations to elucidate ion channel function

我们体内的数万亿个细胞必须相互交流。信息可以通过带电粒子（离子）进出细胞产生的微小电信号来传递。离子通过称为离子通道的成孔蛋白质穿过细胞膜。离子通道具有多个亚基和许多运动部件，并且响应于各种刺激而打开。目前，我们对离子通道功能的分子机制的理解存在很大的差距，这阻碍了我们对基本生理过程的了解。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起着至关重要的作用，例如，在疼痛感测和认知功能中，或在肌肉细胞中，例如对于稳定的心律至关重要。控制这些离子通道功能的机制正在研究中。我们的短期目标是了解这些通道机制中与激活和调节有关的具体细节。这将提供基本的见解，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如何在天然环境中工作的原子级描述，有助于详细了解离子通道生理学。离子通道打开和关闭;因此，动力学对功能至关重要。实验方法可以确定三维结构，提供离子通道的模型作为时间快照。不幸的是，这些仍然是特定国家的图像。为了充分理解离子通道功能的分子机制，我们必须研究将状态联系在一起的动力学。我的研究使用计算机模拟，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，将静态结构带入生活。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激活类型和另一个通道的两种调节类型。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级描述。我们的研究是推动该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留下了空白。模拟弥合了这一差距，因为结构为可以解释功能实验的模拟提供了输入。 了解生理功能的分子细节可能会导致病理生理学的见解。因此，我们的基础NSE研究结果最终可以转移到最终用户，以改善两个离子通道的药物发现，这些离子通道具有巨大的未开发的药物潜力。这将有利于加拿大制药业和加拿大人口，通过设计改进的药物来治疗，疼痛中风和心律失常

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.