AUTHOR=Costa Flavio , Guardiani Carlo , Giacomello Alberto 

TITLE=Exploring Kv1.2 Channel Inactivation Through MD Simulations and Network Analysis

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=8

YEAR=2021

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2021.784276

DOI=10.3389/fmolb.2021.784276

ISSN=2296-889X

ABSTRACT=<p>The KCNA2 gene encodes the K<sub><italic>v</italic></sub>1.2 channel, a mammalian Shaker-like voltage-gated K<sup>+</sup> channel, whose defections are linked to neuronal deficiency and childhood epilepsy. Despite the important role in the kinetic behavior of the channel, the inactivation remained hereby elusive. Here, we studied the K<sub><italic>v</italic></sub>1.2 inactivation <italic>via</italic> a combined simulation/network theoretical approach that revealed two distinct pathways coupling the Voltage Sensor Domain and the Pore Domain to the Selectivity Filter. Additionally, we mutated some residues implicated in these paths and we explained microscopically their function in the inactivation mechanism by computing a contact map. Interestingly, some pathological residues shown to impair the inactivation lay on the paths. In summary, the presented results suggest two pathways as the possible molecular basis of the inactivation mechanism in the K<sub><italic>v</italic></sub>1.2 channel. These pathways are consistent with earlier mutational studies and known mutations involved in neuronal channelopathies.</p>