Modeling the syn -cycle in the light activated opening of the channelrhodopsin-2 ion channel

• Published in: RSC advances Vol. 12; no. 11; pp. 6515 - 6524
• Main Authors: Xin, Qi, Cheng, Jie, Wang, Hongwei, Zhang, Wenying, Lu, Hong, Zhou, Junpeng, Lo, Glenn V, Dou, Yusheng, Yuan, Shuai
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 22-02-2022; The Royal Society of Chemistry
• Subjects: Chemistry; Crystal structure; Dark adaptation; Dynamic structural analysis; Homology; Hydrogen bonds; Imines; Ion channels; Isomerization; Molecular dynamics
• ISSN: 2046-2069; 2046-2069
• DOI: 10.1039/d1ra08521b

The ion channel of channelrhodopsin-2 (ChR2) is activated by absorbing light. The light stimulates retinal to isomerize to start the photocycle. There are two pathways for photocycles, which are caused by isomerization of the retinal from all-
, 15-
to 13-
, 15-
in the dark-adapted state (
-cycle) and from 13-
, 15-
to all-
, 15-
in the light-adapted state (
-cycle). In this work, the structure of the
-cycle intermediate and mechanism of channel opening were studied by molecular dynamics (MD) and steered molecular dynamics (SMD) simulations. Due to the lack of crystal structure of intermediates in the
-cycle of ChR2, the intermediate models were constructed from the homologous intermediates in the
-cycle. The isomerization of retinal was shown to cause the central gate (CG) hydrogen bond network to rearrange, cutting the link between TM2 and TM7. TM2 is moved by the intrahelical hydrogen bond of E90 and K93, and induced the intracellular gate (ICG) to expand. The ion penetration pathway between TM1, TM2, TM3 and TM7 in the P500* state was observed by MD simulations. However, this channel is not fully opened compared with the homologous P500 state in the
-cycle. In addition, the protons on Schiff bases were found to be unable to form hydrogen bonds with the counter residues (E123 and D253) in the P500* state, preventing an evolution of the P500* state to a P390-like state in the
-cycle.