Grant: Discovery Grants Program - Individual

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.