Gating Mechanism of the Voltage-Gated Proton Channel Studied by Molecular Dynamics Simulations

Molecules

卷:27

Thi Tuong Vy Phan¹  Myunggi Yi² 

[1] Center for Advanced Chemistry, Institute of Research and Development, Duy Tan University, 03 Quang Trung, Hai Chau, Danang 550000, Vietnam;

[2] Department of Biomedical Engineering, Pukyong National University, Busan 48513, Korea;

关键词: gating mechanism;    Hv1 proton channel;    water-wire;    molecular dynamics simulations;   

DOI  :  10.3390/molecules27072277

来源: DOAJ

【 摘 要 】

The voltage-gated proton channel Hv1 has important roles in proton extrusion, pH homeostasis, sperm motility, and cancer progression. The Hv1 channel has also been found to be highly expressed in cell lines and tissue samples from patients with breast cancer. A high-resolution closed-state structure has been reported for the mouse Hv1 chimera channel (mHv1cc), solved by X-ray crystallography, but the open-state structure of Hv1 has not been solved. Since Hv1 is a promising drug target, various groups have proposed open conformations by molecular modeling and simulation studies. However, the gating mechanism and the open-state conformation under the membrane potential are still debate. Here, we present a molecular dynamics study considering membrane potential and pH conditions. The closed-state structure of mHv1cc was used to run molecular dynamics (MD) simulations with respect to electric field and pH conditions in order to investigate the mechanism of proton transfer. We observed a continuous hydrogen bond chain of water molecules called a water-wire to be formed through the channel pore in the channel opening, triggered by downward displacement of the S2 helix and upward movement of the S4 helix relative to other helices. Due to the movement of the S2 and S4 helices, the internal salt bridge network was rearranged, and the hydrophobic gating layers were destroyed. In line with previous experimental and simulation observations, our simulation results led us to propose a new gating mechanism for the Hv1 proton channel, and may provide valuable information for novel drug discovery.

【 授权许可】

Unknown