Simulating The Activation Of Voltage Sensing Domain For A Voltage-gated Sodium Channel

Voltage-gated sodium(Na_V)channels control the transmembrane influx of sodium ions and are in charge of initiation of action potentials in excitable cells.Na_Vchannels play vital roles in the rhythm regulation of heart and the signal transduction of neurons.Mutations in Na_Vchannel genes are associated with diseases caused by dysfunction of excitable tissues.Upon activation of a Na_Vchannel,the change of transmembrane voltage triggers conformational change of the voltage sensing domain(VSD),which then elicits opening of the pore domain and thus allows an influx of sodium ions.Description of this process with atomistic details is in urgent demand.In this work,we performed unbiased conformational sampling of the VSD of a prokaryotic Na_Vchannel using an additive force field and a polarizable force field re-spectively.We observed the partial activation process of the VSD.Structures suggest remarkable relative sliding of the S4 helix against S1-S3 with the twisting/screwing of S4 helix.Gating charge residues sequentially break and form ionic/hydrogen bonds with conserved residues and lipid head groups.We not only observed the conformational change of the VSD from resting to preactive state,but also rigorously estimated the free energy profile along the identified reaction pathway.Comparison with the control simulation using an additive force field indi-cates that voltage-gating thermodynamics of Na_Vchannels may be inaccurately described without considering the electrostatic polarization effect.In addition,we sequentially applied wavelet transform-based curve clustering(WTCC)and time-lagged independent component analysis(tICA)on the simulation of ac-tivation,which generated proper long-time scale motions.Markov state models(MSMs),constructed from the motions,showed good thermodynamics of VSD activation.Com-pared with rigorously free energy calculation profile,this workflow required much less computational resource.