Molecular Mechanism Of PH Dependent Ion Selectivity Of K2P Channels

TWIK-1 is a subtype of the Two-Pore Domain Potassium Channels family,which maintains membrane potential and plays a key role in a variety of cellular functions.TWIK-1 channel is detected in many organs and responds to various physical and chemical stimuli such as mechanical stretch,arachidonic acid,lipids,and volatile anesthetics.Moreover,decreases of p H change the ion selectivity of TWIK-1.While the mechanism of how low pH regulates the ion selectivity of K2 P channels is not well understood.Here,we combined molecular dynamics(MD)with Steered molecular dynamics(SMD)simulations and got the following conclusions:1.We confirmed that sodium ions falling into the selective filter is more easily at low pH.The conformation changes increase the permeability of sodium ions.2.Our data show that the His-112 at the mouth of selective filter plays an important role in ion selectivity.His-112 with different protonation states change the interactions around it.3.The electrostatic repulsion from charged amino acids with same charge sign contributes to destabilize the ?-helical structures.This work may provide insights on the understanding of how low pH affects the ion selectivity of K2 P channels,and imply that these acid-sensitive K2 P channels may regulate cellular function with dynamic changes in their ion selectivity.