Biophysical Society Thematic Meeting | Ascona 2026

Mechanobiology of Infection

Poster Abstracts

6-POS Board 6 PORE LIPID MODIFICATIONS MODULATE MECHANOSENSITIVE CHANNEL FOR ENHANCED SINGLE-MOLECULE SENSING Chen Chen 1 ; Changjian Zhao 1 ; Xingyu Mou 1 ; Huanxiang Liu 2 ; Rui Bao 1 ; Jianping Wu 3 ; Jia Geng 1 ; 1 Sichuan University, West China School of Medicine, Chengdu, China 2 Macao Polytechnic University, Centre for Artificial Intelligence Driven Drug Discovery, Macau, China 3 Westlake University,, Zhejiang Provincial Laboratory of Life Sciences and Biomedicine, Hangzhou, China Modifying transmembrane channels is essential for enhancing functionality. Current modification methods often require chemical reactions or protein engineering, which can increase technical complexity and workload. The inner transmembrane region of mechanosensitive channel of smaller conductance (MscS) can bind lipid molecules, referred to as pore lipids, offering an opportunity for fine-tuning channel properties and improving sensing performance. Here, we find that lipid-like molecules such as detergents can modulate Pseudomonas aeruginosa MscS (PaMscS) channel function, and altering the detergent changes channel properties; based on this, we developed a strategy to enhance sensing capability through detergent functionalization. We leveraged lipid-like molecules, specifically detergents, to replace pore lipids, introducing specific chemical groups into the MscS channel. Using Cryo-electron Microscopy (cryo-EM), we determined the structure of PaMscS demonstrating that n-Dodecyl- β D-maltopyranoside (DDM) bind stably at the entrance of the hydrophobic pathway. Single channel recordings confirmed that detergent substitution within the pore alters channel conductance and gating behavior. Molecular dynamics simulations further revealed that detergent modifications adjust the tilt of the TM1-TM2 helices, influencing the channel state. By modifying MscS with different detergents, we tailored its properties, enabling selective detection of target molecules at the single-molecule level. This approach capitalizes on the intrinsic characteristics of MscS and lipid-like molecules, providing a convenient and efficient method for nanopore modification without complex chemical reactions or protein recombination.

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