Molecular Mechanism Of Calcium Ions Binding And Triggering The Conformational Changes Of BK Channel Gating

BK channels,known as large conductance,Ca²⁺-activated potassium channels,are widely expressed in the body of animals and play important roles in many physiological processes.Loss-function of BK channels will lead to ion channel diseases.BK channels activation can be regulated by various intracellular chemical ligands such as Ca²⁺ and others.Electrophysiological experiments and crystal structures indicate that calcium ions bind at the gating ring,which triggers the gating of BK channels.However,crystal structures only represent static conformation and can't reflect dynamics behavior of gating process.Electrophysiological experiments can reflect the relationship of currents and voltage,but can neither reveal molecular mechanism of Ca²⁺-induced conformational changes of BK channels gating ring nor identify the transmission pathway of interaction with Ca²⁺ opening BK channels.Here,we applied Homology Model,Molecular Dynamics?MD?and Targeted MD to the integrated gating ring of BK channels and put emphasis on allosteric-activation mechanism of BK channel gating ring triggered by calcium ions.This research provides theoretic support for promoting the drug design targeting at BK channels.We have got the valuable conclusions as followed:1.We have constructed two 3-dimentional structures of BK gating ring,closed and open states.2.We applied Molecular Dynamics?MD?and Targeted MD to the integrated gating ring of BK channels,and achieved the transition from the closed state to open state.3.Compared with the Ca²⁺ bowl at RCK2 domain,the RCK1 Ca²⁺ sites?RCK1 sites?make more contribution to opening the channel.It is the rotatory motion and open motion of the gating rings that are thought to pull the bundle crossing gate to open ultimately.4.We identified the transmission pathway of interaction-networks,which exquisitely regulates the conformational changes during the opening of BK channels by Ca²⁺.