TY - JOUR
T1 - Effects of β-subunit on gating of a potassium ion channel
T2 - Molecular simulations of cardiac IKs activation
AU - Xu, Jiajing
AU - Rudy, Yoram
N1 - Funding Information:
We appreciate greatly stimulating and illuminating discussions with Drs. Ali Nekouzadeh, Ashwin Mohan, Smiruthi Ramasubramanian, Leonid Livshitz, Jianmin Cui and Jonathan Silva. We thank Prof. Bernard Attali from Tel Aviv University for providing experimental data. Maya Bera and Malcolm Tobias provided essential computational support. The study was supported by NIH–National Heart, Lung, and Blood Institute grants [R01-HL-049054 and R01-HL-033343 to Y. Rudy]. Dr. Rudy is the Fred Saigh Distinguished Professor at Washington University. Computations were performed using facilities in the Rudy Lab and Washington University Center for High Performance Computing, which were partially supported through grant NCRR 1S10RR022984-01A1.
Funding Information:
We appreciate greatly stimulating and illuminating discussions with Drs. Ali Nekouzadeh, Ashwin Mohan, Smiruthi Ramasubramanian, Leonid Livshitz, Jianmin Cui and Jonathan Silva. We thank Prof. Bernard Attali from Tel Aviv University for providing experimental data. Maya Bera and Malcolm Tobias provided essential computational support. The study was supported by NIH – National Heart, Lung, and Blood Institute grants [ R01-HL-049054 and R01-HL-033343 to Y. Rudy]. Dr. Rudy is the Fred Saigh Distinguished Professor at Washington University. Computations were performed using facilities in the Rudy Lab and Washington University Center for High Performance Computing, which were partially supported through grant NCRR 1S10RR022984-01A1 .
Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/11
Y1 - 2018/11
N2 - Dynamic conformational changes of ion channel proteins during activation gating determine their function as carriers of current. The relationship between these molecular movements and channel function over the physiological timescale of the action potential (AP) has not been fully established due to limitations of existing techniques. We constructed a library of possible cardiac IKs protein conformations and applied a combination of protein segmentation and energy linearization to study this relationship computationally. Simulations reproduced the effects of the beta-subunit (KCNE1) on the alpha-subunit (KCNQ1) dynamics and function, observed in experiments. Mechanistically, KCNE1 increased the probability of “visiting” conducting pore conformations on activation trajectories, thereby increasing IKs current. KCNE1 slowed IKs activation by impeding the voltage sensor (VS) movement and reducing its coupling to pore opening. Conformational changes along activation trajectories determined that the S4-S5 linker (S4S5L) plays an important role in these modulatory effects by KCNE1. Integration of these molecular structure-based IKs dynamics into a model of human cardiac ventricular myocyte, revealed that KCNQ1-KCNE1 interaction is essential for normal AP repolarization.
AB - Dynamic conformational changes of ion channel proteins during activation gating determine their function as carriers of current. The relationship between these molecular movements and channel function over the physiological timescale of the action potential (AP) has not been fully established due to limitations of existing techniques. We constructed a library of possible cardiac IKs protein conformations and applied a combination of protein segmentation and energy linearization to study this relationship computationally. Simulations reproduced the effects of the beta-subunit (KCNE1) on the alpha-subunit (KCNQ1) dynamics and function, observed in experiments. Mechanistically, KCNE1 increased the probability of “visiting” conducting pore conformations on activation trajectories, thereby increasing IKs current. KCNE1 slowed IKs activation by impeding the voltage sensor (VS) movement and reducing its coupling to pore opening. Conformational changes along activation trajectories determined that the S4-S5 linker (S4S5L) plays an important role in these modulatory effects by KCNE1. Integration of these molecular structure-based IKs dynamics into a model of human cardiac ventricular myocyte, revealed that KCNQ1-KCNE1 interaction is essential for normal AP repolarization.
KW - Cardiac action potential
KW - Ion channels
KW - Molecular simulation
KW - Protein dynamics
KW - Protein structure-function
UR - http://www.scopus.com/inward/record.url?scp=85054437466&partnerID=8YFLogxK
U2 - 10.1016/j.yjmcc.2018.10.003
DO - 10.1016/j.yjmcc.2018.10.003
M3 - Article
C2 - 30292722
AN - SCOPUS:85054437466
SN - 0022-2828
VL - 124
SP - 35
EP - 44
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
ER -