Characterizing the functional dynamics of the Leak Potassium channel h-TRAAK through Molecular Dynamics Simulations under physiological conditions

Two Pore domain K+ channels (K2P) are a specific family of channels whose functionality is finely tuned by a rich ensemble of chemical and physical stimuli. The ionic currents produced by these proteins are usually referred as ‘’leak’’ or ‘’background’’ potassium currents because they stabilize the resting potential of membranes to highly negative values close to the K+ equilibrium potential. In particular, the human TRAAK channel (Twik Related Arachidonic Acid K+ channel) is influenced by chemicals (anesthetics or drugs), and physical agents (pH, temperature, membrane stretching or bending). Although the firsts experimental findings date back to early ‘00 a full comprehension of the gating mechanism and ion transport is still missing. Among the most influential theories on gating, we mention the two states hypothesis suggested by MacKinnon thanks to the crystal structure availability. The existence of an atomistic model paved the way to furthers investigations, as well by using theoretical approaches. In this context, exploiting in silico techniques belonging to computational biophysics, we provided a comprehensive characterization of the channel behaviour. Advanced simulating conditions were used, with the purpose of mimicking as close as possible the real protein behaviour, and some of those key-biases playing a modulation role of channel activity. By using Molecular Dynamics simulations, several protocols were applied to simulate hTRAAK in presence of different conditions: i) membrane stretching, ii) ions concentration gradients, iii) applied electrostatic potential. These strategies were chosen to gain new insights into the putative conductive state of the channel, promoting the translocation of K+ ions through it.