Single-molecule tweezers decode hidden dimerization patterns of membrane proteins within lipid bilayers

Victor W. Sadongo, Eojin Kim, Seoyoon Kim, W. C. Bhashini Wijesinghe, Taeseung Lee, Jeong-Mo Choi and Duyoung Min ()
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Victor W. Sadongo: Ulsan National Institute of Science and Technology
Eojin Kim: Ulsan National Institute of Science and Technology
Seoyoon Kim: Ulsan National Institute of Science and Technology
W. C. Bhashini Wijesinghe: Ulsan National Institute of Science and Technology
Taeseung Lee: Pusan National University
Jeong-Mo Choi: Pusan National University
Duyoung Min: Ulsan National Institute of Science and Technology

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Dimerization of transmembrane (TM) proteins is a fundamental process in cellular membranes, central to numerous physiological and pathological pathways, and increasingly recognized as a promising therapeutic target. Although often described as a simple two-state transition from monomers to dimers, the process following monomer diffusion—referred to as post-diffusion dimerization—is likely more intricate due to complex inter-residue interactions. Here, we present a single-molecule tweezer platform that directly profiles these post-diffusion transitions during TM protein dimerization. This approach captures reversible dimerization events of individual TM dimers, revealing previously hidden intermediate states that emerge after monomer diffusion. By integrating measurements of intermediates, kinetics, and energy landscapes with molecular dynamics simulations, we delineate the dimerization pathway and dissect how residue interactions and lipid bilayers influence the process. Furthermore, our platform allows for the targeted analysis of localized perturbations—such as those induced by peptide binding or site-directed mutagenesis—demonstrating its utility for probing the mechanisms of TM dimer-targeting therapeutics at single-molecule resolution.

Date: 2025
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DOI: 10.1038/s41467-025-62852-1

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