Tracking a complete cycle of a molecular voltage sensor with combinations of electrophysiology and simulation

Ion channels are some of the most important membrane proteins, with very direct functional effect on the transport in and out of cells. They are also amazing microscopic machines where a few symmetric alpha helices makes it possible to control the flux of ions through small variations in the membrane potential, or by binding other molecules. Some of the most common channels conduct potassium ions, and for these the whole gating is controlled by a charged segment called S4 that somehow must move when the voltage across the cell membrane changes. However, despite decades of work on this system, it has this far only been possible to crystallize the channel in the open state – until recently we did not understand what happens during gating (opening/closing).

Here, I will discuss our approach of combining computer-based molecular simulation methods with traditional experimental methods, in particular electrophysiology, to systematically produce new models and test their validity. This has enabled us to derive dozens of new constraints as the molecular voltage sensor adopts different states, which in turn makes it possible to create a direct movie of how the channel moves between different states. The availability of molecular models for all these states is an important step towards understanding the effect of drugs on the channels, and in particular develop new drugs to specifically stabilize open or closed states to compensate for disease-related mutations.