Membrane Proteins; Molecular Biophysics; High-resolution Microscopy; Quantitative Measurements; Bionanotechnology; Biological Membranes; Receptor-Ligand Interactions
Mulvihill Estefania, Pfreundschuh Moritz, Thoma Johannes, Ritzmann Noah, Müller Daniel J. (2019), High-Resolution Imaging of Maltoporin LamB while Quantifying the Free-Energy Landscape and Asymmetry of Sugar Binding, in Nano Letters
, 19(9), 6442-6453.
Sapra K Tanuj, Spoerri Patrizia M, Engel Andreas, Alsteens David, Müller Daniel J (2019), Seeing and sensing single G protein-coupled receptors by atomic force microscopy, in Current Opinion in Cell Biology
, 57, 25-32.
Serdiuk Tetiana, Steudle Anja, Mari Stefania A., Manioglu Selen, Kaback H. Ronald, Kuhn Andreas, Müller Daniel J. (2019), Insertion and folding pathways of single membrane proteins guided by translocases and insertases, in Science Advances
, 5(1), eaau6824-eaau6824.
Thoma Johannes, Manioglu Selen, Kalbermatter David, Bosshart Patrick D., Fotiadis Dimitrios, Müller Daniel J. (2018), Protein-enriched outer membrane vesicles as a native platform for outer membrane protein studies, in Communications Biology
, 1(1), 23-23.
Thoma Johannes, Sapra K. Tanuj, Müller Daniel J. (2018), Single-Molecule Force Spectroscopy of Transmembrane β-Barrel Proteins, in Annual Review of Analytical Chemistry
, 11(1), 375-395.
Mulvihill Estefania, Sborgi Lorenzo, Mari Stefania A, Pfreundschuh Moritz, Hiller Sebastian, Müller Daniel J (2018), Mechanism of membrane pore formation by human gasdermin‐D, in The EMBO Journal
, 37(14), e98321.
Spoerri Patrizia M., Kato Hideaki E., Pfreundschuh Moritz, Mari Stefania A., Serdiuk Tetiana, Thoma Johannes, Sapra K. Tanuj, Zhang Cheng, Kobilka Brian K., Müller Daniel J. (2018), Structural Properties of the Human Protease-Activated Receptor 1 Changing by a Strong Antagonist, in Structure
, 26(6), 829-838.e4.
Wegmann Susanne, Eftekharzadeh Bahareh, Tepper Katharina, Zoltowska Katarzyna M, Bennett Rachel E, Dujardin Simon, Laskowski Pawel R, MacKenzie Danny, Kamath Tarun, Commins Caitlin, Vanderburg Charles, Roe Allyson D, Fan Zhanyun, Molliex Amandine M, Hernandez‐Vega Amayra, Muller Daniel, Hyman Anthony A, Mandelkow Eckhard, Taylor J Paul, Hyman Bradley T (2018), Tau protein liquid–liquid phase separation can initiate tau aggregation, in The EMBO Journal
, 37(7), e98049.
Laskowski Pawel R., Pfreundschuh Moritz, Stauffer Mirko, Ucurum Zöhre, Fotiadis Dimitrios, Müller Daniel J. (2017), High-Resolution Imaging and Multiparametric Characterization of Native Membranes by Combining Confocal Microscopy and an Atomic Force Microscopy-Based Toolbox, in ACS Nano
, 11(8), 8292-8301.
Thoma Johannes, Ritzmann Noah, Wolf Dominik, Mulvihill Estefania, Hiller Sebastian, Müller Daniel J. (2017), Maltoporin LamB Unfolds β Hairpins along Mechanical Stress-Dependent Unfolding Pathways, in Structure
, 25(7), 1139-1144.e2.
Pfreundschuh Moritz, Harder Daniel, Ucurum Zöhre, Fotiadis Dimitrios, Müller Daniel J. (2017), Detecting Ligand-Binding Events and Free Energy Landscape while Imaging Membrane Receptors at Subnanometer Resolution, in Nano Letters
, 17(5), 3261-3269.
Dufrêne Yves F., Ando Toshio, Garcia Ricardo, Alsteens David, Martinez-Martin David, Engel Andreas, Gerber Christoph, Müller Daniel J. (2017), Imaging modes of atomic force microscopy for application in molecular and cell biology, in Nature Nanotechnology
, 12(4), 295-307.
Alsteens David, Müller Daniel J., Dufrêne Yves F. (2017), Multiparametric Atomic Force Microscopy Imaging of Biomolecular and Cellular Systems, in Accounts of Chemical Research
, 50(4), 924-931.
van Pee Katharina, Mulvihill Estefania, Müller Daniel J., Yildiz Özkan (2016), Unraveling the Pore-Forming Steps of Pneumolysin from Streptococcus pneumoniae, in Nano Letters
, 16(12), 7915-7924.
Serdiuk Tetiana, Balasubramaniam Dhandayuthapani, Sugihara Junichi, Mari Stefania A, Kaback H Ronald, Müller Daniel J (2016), YidC assists the stepwise and stochastic folding of membrane proteins, in Nature Chemical Biology
, 12(11), 911-917.
Hilbert Manuel, Noga Akira, Frey Daniel, Hamel Virginie, Guichard Paul, Kraatz Sebastian H. W., Pfreundschuh Moritz, Hosner Sarah, Flückiger Isabelle, Jaussi Rolf, Wieser Mara M., Thieltges Katherine M., Deupi Xavier, Müller Daniel J., Kammerer Richard A., Gönczy Pierre, Hirono Masafumi, Steinmetz Michel O. (2016), SAS-6 engineering reveals interdependence between cartwheel and microtubules in determining centriole architecture, in Nature Cell Biology
, 18(4), 393-403.
Membrane proteins are prominent actors in living cells providing unique and essential functions for basic cellular processes. This is the main reason why membrane proteins reach a high interest in biological, medical and pharmacological research. One key question of these fields is how ligands (or drugs or molecular compounds) bind to native membrane proteins thereby modulating their functional state. Although well-established methods can solve the structure of liganded membrane proteins, microscopic (or more suitable ‘nanoscopic’) methods that allow imaging single membrane proteins at nanometer resolution (˜1 nm) and at the same time structurally quantifying the interaction forces of a given ligand hardly exist. Moreover, high-resolution nanoscopic and spectroscopic approaches that enable to structurally observe membrane proteins at nanometer resolution and to simultaneously map the energy landscape of a binding ligand do not exist. Importantly, such insight would contribute significantly to the chemical and physical understanding of how ligands, drugs and other molecular compounds interact with native membrane proteins.Here we intend to develop and establish multifunctional high-resolution atomic force microscopy (AFM) that allows to image single native membrane proteins at sub-nanometer resolution and at the same time to quantify the interaction forces of a given ligand with a membrane protein. Therefore, we will employ force-distance (FD) curve-based AFM (FD-based AFM), which we have recently established to image the surface of biological membranes and membrane proteins at a resolution of =1 nm and to simultaneously map the interactions of single membrane proteins in three dimensions. We intend to further develop this method to detect how a ligand finds its way to specifically bind and to unbind from the receptor’s binding pocket. To do so a ligand is tethered to the AFM stylus and the interaction forces of the ligand with the membrane protein are localized and quantified while imaging the membrane protein at high-resolution. These interaction forces are then mapped in three-dimensions (3D) to the membrane protein at sub-nanometer resolution and pico-newton sensitivity. Because the method will also be applicable to quantify and to structurally map the interaction of any given molecule with membrane proteins or other biological surfaces it is of general interest for a plethora of biological systems. In initial experiments we could show the feasibility of this method at a relatively low resolution of ˜5 nm. However, because the interaction forces of ligands and membrane proteins (or of any other biological system) depend on the rate at which they are probed , the quantification of forces is relative. An approach towards providing an absolute measure would be to determine the energy landscape of a ligand interacting with a membrane protein. Thus, we take the challenge to develop FD-based AFM into a method, which allows imaging native proteins at high-resolution and to structurally map the energy landscape of a ligand interacting with a native protein. Once developed, this multifunctional and nanotechnological tool will be applicable to gain unique structural, kinetic and energetic insights of ligands interacting with membrane receptors, or of any given molecule interacting with any biological system.