Mechanism Of Weak Interactions Regulating Gating Of Inwardly Rectifying K⁺（kir） Channels

Ion channels are widely distributed in the membrane both of the eukaryotic and prokaryotic cells and play vital roles in variety of physiological processes. The channel proteins transfer from different conformations, known as gating, according to the external stimuli and allow specific ions passing through them. As one of the important branches in the ion channel superfamily, the Kir channel is one of the key way of the K+ across the membrane. However, the molecular mechanism and structural basis of the conformation transition during Kir channel gating is still obscure.In this study, Combining the theoretical modeling, molecular dynamics simulation with electrophysiological experiments was used to understand the molecular mechanism of how the weak-electric interactions modulate the gating of Kir channels. To strives for a more in-depth pathological understanding of ion channel diseases and promotes the progress of targeted drug design and treatment. The present study will increase the combination of life sciences and physics, especially the combination of biological experiments and theoretical analysis. The main results obtained are as follows:1. Two type of interactions that are electrostatic interaction between the membrane phospholipid PIP2 and weak interaction in inner channels is collectively known as the weak-electric interactions. The relationship between the gating mechanism of the Kir channel and weak-electric interactions was proposed. The conformational transition pathway was identified in the gating of the Kir2.1 channel by analyzing these interactions. A novel gating model is proposed which will shed light on understanding the molecular mechanism of the gating Kir channels.2. It was verified to affect the gating mechanism of the Kir channels by the key amino acids. Our data show that the weak interaction could change the key amino acids flexibility, achieved the long-range transmission.3. An interactive approach between homology modeling, molecular dynamics and electrophysiological approach was applied to understand the molecular mechanism of the voltage-dependent blockade of Kir2.2 by extracellular Mg2+. The data show that the surface charged residues at the external mouth of Kir channels reduce the blockage of Kir2.2 by extracellular Mg2+ and enhance the inward K+ currents.4. To explain the molecular mechanism by which the leading compounds targeting drug molecules(celecoxib and QO-58) modulate the gating of Kv7 channel. The binding sites of these small molecules were identified. The interaction between the channel and the molecules was determined. The data sustain the molecular drug design in theory.