中国物理B ›› 2025, Vol. 34 ›› Issue (12): 128704-128704.doi: 10.1088/1674-1056/ae172d

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Molecular dynamics simulations reveal the activation mechanism of human TMEM63A induced by lysophosphatidylcholine insertion

Zain Babar2†, Junaid Wahid2†, Xiaofei Ji(季晓飞)1, Huilin Zhao(赵慧琳)1, Hua Yu(于华)3, and Dali Wang(王大力)1‡   

  1. 1 School of Basic Medical Sciences, Binzhou Medical University, Yantai 264003, China;
    2 School of Foreign Languages and International Exchange, Binzhou Medical University, Yantai 264003, China;
    3 College of Plant Protection, Shandong Agricultural University, Tai'an 271018, China
  • 收稿日期:2025-05-30 修回日期:2025-07-30 接受日期:2025-10-24 发布日期:2025-11-25
  • 通讯作者: Dali Wang E-mail:dlwang@bzmc.edu.cn
  • 基金资助:
    This work was supported by the Natural Science Foundation of Shandong Province (Grant Nos. ZR2024QC388 and ZR2023MH101) and Science and Technology Support Plan for Youth Innovation of Colleges and Universities of Shandong Province (Grant No. 2020KJK006). The work was carried out at National Supercomputer Center in Tianjin, and the calculations were performed on Tianhe new generation supercomputer.

Molecular dynamics simulations reveal the activation mechanism of human TMEM63A induced by lysophosphatidylcholine insertion

Zain Babar2†, Junaid Wahid2†, Xiaofei Ji(季晓飞)1, Huilin Zhao(赵慧琳)1, Hua Yu(于华)3, and Dali Wang(王大力)1‡   

  1. 1 School of Basic Medical Sciences, Binzhou Medical University, Yantai 264003, China;
    2 School of Foreign Languages and International Exchange, Binzhou Medical University, Yantai 264003, China;
    3 College of Plant Protection, Shandong Agricultural University, Tai'an 271018, China
  • Received:2025-05-30 Revised:2025-07-30 Accepted:2025-10-24 Published:2025-11-25
  • Contact: Dali Wang E-mail:dlwang@bzmc.edu.cn
  • About author:2025-128704-250958.pdf
  • Supported by:
    This work was supported by the Natural Science Foundation of Shandong Province (Grant Nos. ZR2024QC388 and ZR2023MH101) and Science and Technology Support Plan for Youth Innovation of Colleges and Universities of Shandong Province (Grant No. 2020KJK006). The work was carried out at National Supercomputer Center in Tianjin, and the calculations were performed on Tianhe new generation supercomputer.

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摘要： OSCA/TMEM63 protein families are recognized as typical mechanosensitive (MS) ion channels in both plants and animals. Resolved OSCA and TMEM63 structures have revealed that these channels are forming dimer and monomer, respectively. Despite the distinguished architectures, OSCA and TMEM63 serve similar functions in multiple physiological processes. Recently, human TMEM63A (hTMEM63A) structure was identified, allowing for investigation into the activation mechanism of hTMEM63A through molecular dynamics (MD) simulations. In this study, we performed multi-scale MD simulations toward hTMEM63A, aiming to reveal how lipid binding regulates hTMEM63A activation. Our results identified two regions on the surface of hTMEM63A, exhibiting a preference for lysophosphatidylcholine (LPC) lipids. Further conformation analyses clarified the activation mechanism of hTMEM63A induced by LPC insertion. These simulation results provide detailed insights into the hTMEM63A-lipid interaction and significant conformational changes associated with hTMEM63A gating, thereby shed lights on the MS ion channel activation mechanism driven by lipid plugging.

关键词: molecular dynamics simulation, membrane proteins, conformational changes, protein-membrane interactions

Abstract: OSCA/TMEM63 protein families are recognized as typical mechanosensitive (MS) ion channels in both plants and animals. Resolved OSCA and TMEM63 structures have revealed that these channels are forming dimer and monomer, respectively. Despite the distinguished architectures, OSCA and TMEM63 serve similar functions in multiple physiological processes. Recently, human TMEM63A (hTMEM63A) structure was identified, allowing for investigation into the activation mechanism of hTMEM63A through molecular dynamics (MD) simulations. In this study, we performed multi-scale MD simulations toward hTMEM63A, aiming to reveal how lipid binding regulates hTMEM63A activation. Our results identified two regions on the surface of hTMEM63A, exhibiting a preference for lysophosphatidylcholine (LPC) lipids. Further conformation analyses clarified the activation mechanism of hTMEM63A induced by LPC insertion. These simulation results provide detailed insights into the hTMEM63A-lipid interaction and significant conformational changes associated with hTMEM63A gating, thereby shed lights on the MS ion channel activation mechanism driven by lipid plugging.

Key words: molecular dynamics simulation, membrane proteins, conformational changes, protein-membrane interactions

中图分类号:  (Molecular dynamics simulation)

  • 87.15.ap
87.14.ep (Membrane proteins) 87.15.hp (Conformational changes) 87.15.kt (Protein-membrane interactions)