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

doi:10.1088/1674-1056/ae172d

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.

Keywords: molecular dynamics simulation membrane proteins conformational changes protein-membrane interactions

Received: 30 May 2025
Revised: 30 July 2025
Accepted manuscript online: 24 October 2025

PACS:	87.15.ap	(Molecular dynamics simulation)
	87.14.ep	(Membrane proteins)
	87.15.hp	(Conformational changes)
	87.15.kt	(Protein-membrane interactions)

Fund: 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.

Corresponding Authors: Dali Wang
E-mail: dlwang@bzmc.edu.cn

About author: 2025-128704-250958.pdf

Cite this article:

Zain Babar, Junaid Wahid, Xiaofei Ji(季晓飞), Huilin Zhao(赵慧琳), Hua Yu(于华), and Dali Wang(王大力) Molecular dynamics simulations reveal the activation mechanism of human TMEM63A induced by lysophosphatidylcholine insertion 2025 Chin. Phys. B 34 128704

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

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