Structure and Sequence-based Computational Approaches to Allosteric Signal Transduction: Application to Electromechanical Coupling in Voltage-gated Ion Channels

Allosteric signaling underlies the function of many biomolecules, including membrane proteins such as ion channels. Experimental methods have enabled specific quantitative insights into the coupling between the voltage sensing domain (VSD) and the pore gate of voltage-gated ion channels, located tens of Ångström apart from one another, as well as pinpointed specific residues and domains that participate in electromechanical signal transmission. Nevertheless, an overall atomic-level resolution picture is difficult to obtain from these methods alone. Today, thanks to the cryo-EM resolution revolution, we have access to high resolution structures of many different voltage-gated ion channels in various conformational states, putting a quantitative description of the processes at the basis of these changes within our close reach. Here, we review computational methods that build on structures to detect and characterize allosteric signaling and pathways. We then examine what has been learned so far about electromechanical coupling between VSD and pore using such methods. While no general theory of electromechanical coupling in voltage-gated ion channels integrating results from all these methods is available yet, we outline the types of insights that could be achieved in the near future using the methods that have not yet been put to use in this field of application.