AlphaFold2 captures conformational transitions in the voltage-gated channel superfamily

Abstract

Voltage-gated ion channels are crucial membrane proteins responsible for the electrical activity in excitable cells. These channels respond to changes in the membrane potential via conformational changes in their voltage-sensing domains (VSDs) that leads to the opening and closing of the ion conduction pore. Since alternative states of the VSDs are difficult to capture via experimental methods, we investigated the application AlphaFold2 to computationally predict structures in a range of intermediate and endpoint states. By generating 600 models for 32 members of the voltage gated cation channel superfamily we show that AlphaFold2 can predict a range of diverse structures of the VSDs that plausibly represent activated, deactivated and intermediate conformations with more diversity seen for some VSDs compared to others. Modelling the full sequence of pseudo-tetrameric channels also produced a range of diverse states in the pore and intracellular regions that potentially represent physiologically relevant states. However, there are some incongruities between certain generated models and resolved cryo-EM structures suggesting that further validation is required to confirm their structural and functional relevance.