Detecting Ligand-Binding Events and Free Energy Landscape while Imaging Membrane Receptors at Subnanometer Resolution.

Pfreundschuh, Moritz; Harder, Daniel; Ucurum Fotiadis, Zöhre; Fotiadis, Dimitrios José; Müller, Daniel J (2017). Detecting Ligand-Binding Events and Free Energy Landscape while Imaging Membrane Receptors at Subnanometer Resolution. Nano letters, 17(5), pp. 3261-3269. American Chemical Society 10.1021/acs.nanolett.7b00941

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Force-distance curve-based atomic force microscopy has emerged into a sophisticated technique for imaging cellular membranes and for detecting specific ligand-binding events of native membrane receptors. However, so far the resolution achieved has been insufficient to structurally map ligand-binding sites onto membrane proteins. Here, we introduce experimental and theoretical approaches for overcoming this limitation. To establish a structurally and functionally well-defined reference sample, we engineer a ligand-binding site to the light-driven proton pump bacteriorhodopsin of purple membrane. Functionalizing the AFM stylus with an appropriate linker-system tethering the ligand and optimizing the AFM conditions allows for imaging the engineered bacteriorhodopsin at subnanometer resolution while structurally mapping the specific ligand-receptor binding events. Improved data analysis allows reconstructing the ligand-binding free energy landscape from the experimental data, thus providing thermodynamic and kinetic insight into the ligand-binding process. The nanoscopic method introduced is generally applicable for imaging receptors in native membranes at subnanometer resolution and for systematically mapping and quantifying the free energy landscape of ligand binding.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Harder, Daniel; Ucurum Fotiadis, Zöhre and Fotiadis, Dimitrios José


500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health




American Chemical Society




Barbara Franziska Järmann-Bangerter

Date Deposited:

08 Mar 2018 15:55

Last Modified:

05 Dec 2022 15:10

Publisher DOI:


PubMed ID:


Uncontrolled Keywords:

Ligand−receptor binding free energy landscape membrane proteins multiparametric imaging single-molecule force spectroscopy single-molecule imaging




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