Nanomechanical Functional Programming of Cellular and Synthetic Systems - NCCR MSE

Nanomechanical Functional Programming of Cellular and Synthetic Systems

Nanotechnological approaches and tools to reprogram nanoreactors and living cells will be developed. Reprogramming will be facilitated using a variety of membrane proteins (pumps, transporters and receptors), genes or peptides.
Nanotechnological approaches and tools to reprogram nanoreactors and living cells will be developed. Reprogramming will be facilitated using a variety of membrane proteins (pumps, transporters and receptors), genes or peptides.

This project programs nanoscopic reaction compartments, nanoreactors, vesicles, nanocontainers, organelles and cells with functional molecular modules that can be of biological, bioengineered or synthetic origin.

A wide variety of functional molecular modules that assemble into a toolbox are and will be established within the NCCR Molecular Systems Engineering. Molecular modules from this toolbox will be used to functionally program molecular factories.

AFM-based nanotechnological methods to manipulate single cells, organelles and proteins at (sub-)nanometre resolution will be further developed and applied to program for example, nanoreactors, organelles or cells with functional modules such as proteins that have been functionally engineered.

The nanomechanical approach to functionally reprogram targets using molecular modules is worldwide unique and enables detergent free, stoichiometric insertion of molecular modules into targets. Subsequently, a method will be developed to program molecular factories by the nanomechanical extraction and for the insertion of functional molecular modules.


I. Incaviglia, S. Herzog, G. Fläschner, N. Strohmeyer, E. Tosoratti, D. J. Müller “Tailoring the Sensitivity of Microcantilevers To Monitor the Mass of Single Adherent Living Cells“ Nano Lett. 2023. [DOI]
S. Hirschi, T. R. Ward, W. P. Meier, D. J. MüllerD. Fotiadis “Synthetic Biology: Bottom-Up Assembly of Molecular Systems“ Chem. Rev. 2022. [DOI]
A. P. Cuny, K. Tanuj Sapra, D. Martinez-Martin, G. Fläschner, J. D. Adams, S. Martin, C. Gerber, F. Rudolf, D. J. Müller “High-resolution mass measurements of single budding yeast reveal linear growth segments“ Nat. Commun. 2022. [DOI]
“A cholesterol analog stabilizes the human beta2-adrenergic receptor nonlinearly with temperature“ Sci. Signal. 2022. [DOI]
S. A. Mari, K. Pluhackova, J. Pipercevic, M. Leipner, S. Hiller, A. Engel, D. J. Müller “Gasdermin-A3 pore formation propagates along variable pathways“ Nat. Commun. 2022. [DOI]
P. R. Laskowski, K. Pluhackova, M. Haase, B. M. Lang, G. Nagler, A. Kuhn, D. J. Müller “Monitoring the binding and insertion of a single transmembrane protein by an insertase“ Nat. Commun. 2021. [DOI]
N. Ritzmann, S. Manioglu, S. Hiller, D. J. Müller “Monitoring the antibiotic darobactin modulating the β-barrel assembly factor BamA“ Structure 2021. [DOI]
A. Viljoen, M. Mathelié-Guinlet, A. Ray, N. Strohmeyer, Y. J. Oh, P. Hinterdorfer, D. J. Müller, D. Alsteens, Y. F. Dufrêne “Force spectroscopy of single cells using atomic force microscopy“ Nat. Rev. Methods Primers 2021. [DOI]
K. Jahnke, N. Ritzmann, J. Fichtler, A. Nitschke, Y. Dreher, T. Abele, G. Hofhaus, I. Platzman, R. R. Schröder, D. J. Müller, J. P. Spatz, K. Göpfrich “Proton gradients from light-harvesting E. coli control DNA assemblies for synthetic cells“ Nat. Commun. 2021. [DOI]
G. Fläschner, C. I. Roman, N. Strohmeyer, D. Martinez-Martin, D. J. Müller “Rheology of rounded mammalian cells over continuous high-frequencies“ Nat. Commun. 2021. [DOI]
K. Bian, C. Gerber, A. J. Heinrich, D. J. Müller, S. Scheuring, Y. Jiang “Scanning probe microscopy“ Nat. Rev. Methods Primers 2021. [DOI]
D. J. Müller, A. C. Dumitru, C. Lo Giudice, H. E. Gaub, P. Hinterdorfer, G. Hummer, J. J. De Yoreo, Y. F. Dufrêne, D. Alsteens “Atomic Force Microscopy-Based Force Spectroscopy and Multiparametric Imaging of Biomolecular and Cellular Systems“ Chem. Rev. 2020. [DOI]
A. J. Lomakin, C. J. Cattin, D. Cuvelier, Z. Alraies, M. Molina, G. P. F. Nader, N. Srivastava, P. J. Sáez, J. M. Garcia-Arcos, I. Y. Zhitnyak, A. Bhargava, M. K. Driscoll, E. S. Welf, R. Fiolka, R. J. Petrie, N. S. De Silva, J. M. González-Granado, N. Manel, A. M. Lennon-Duménil, D. J. Müller, M. Piel “The nucleus acts as a ruler tailoring cell responses to spatial constraints“ Science 2020. [DOI]
B. M. Gaub, K. C. Kasuba, E. Mace, T. Strittmatter, P. R. Laskowski, S. A. Geissler, A. Hierlemann, M. FusseneggerB. RoskaD. J. Müller “Neurons differentiate magnitude and location of mechanical stimuli“ Proc. Natl. Acad. Sci. U.S.A. 2019. [DOI]
R. Schubert, S. Herzog, S. Trenholm, B. RoskaD. J. Müller “Magnetically guided virus stamping for the targeted infection of single cells or groups of cells“ Nat. Protoc. 2019. [DOI]
C. Beerli, A. Yakimovich, S. Kilcher, G. V. Reynoso, G. Fläschner, D. J. Müller, H. D. Hickman, J. Mercer “Vaccinia virus hijacks EGFR signalling to enhance virus spread through rapid and directed infected cell motility“ Nat. Microbiol. 2019. [DOI]
S. Hirschi, N. Fischer, D. Kalbermatter, P. R. Laskowski, Z. Ucurum, D. J. MüllerD. Fotiadis “Design and assembly of a chemically switchable and fluorescently traceable light-driven proton pump system for bionanotechnological applications“ Sci. Rep. 2019. [DOI]
T. Serdiuk, A. Steudle, S. A. Mari, S. Manioglu, H. R. Kaback, A. Kuhn, D. J. Müller “Insertion and folding pathways of single membrane proteins guided by translocases and insertases“ Sci. Adv. 2019. [DOI]
K. T. Sapra, P. M. Spoerri, A. Engel, D. Alsteens, D. J. Müller “Seeing and sensing single G protein-coupled receptors by atomic force microscopy“ Curr. Opin. Cell Biol. 2018, 57:25-32. [DOI]
M. Krieg, G. Fläschner, D. Alsteens, H. E. Gaub, W. H. Roos, G. J. L. Wuite, C. Gerber, Y. F. Dufrêne, D. J. Müller “Atomic force microscopy-based mechanobiology“ Nat. Rev. Phys. 2018. [DOI]
R. Goers, J. Thoma, N. Ritzmann, A. Di Silvestro, C. Alter, G. Gunkel-Grabole, D. FotiadisD. J. Müller, W. Meier “Optimized reconstitution of membrane proteins into synthetic membranes“ Commun. Chem. 2018. [DOI]
J. Thoma, Y. Sun, N. Ritzmann, D. J. Müller “POTRA Domains, Extracellular Lid, and Membrane Composition Modulate the Conformational Stability of the β Barrel Assembly Factor BamA“ Structure 2018. [DOI]
J. Thoma, S. Manioglu, D. Kalbermatter, P. D. Bosshart, D. FotiadisD. J. Müller “Protein-enriched outer membrane vesicles as a native platform for outer membrane protein studies“ Commun. Biol. 2018. [DOI]
R. Schubert, S. Trenholm, K. Balint, G. Kosche, C. S. Cowan, M. A. Mohr, M. Munz, D. Martinez-Martin, G. Fläschner, R. Newton, J. Krol, B. G. Scherf, K. Yonehara, A. Wertz, A. Ponti, A. Ghanem, D. Hillier, K. Conzelmann, D. J. MüllerB. Roska “Virus stamping for targeted single-cell infection in vitro and in vivo“ Nat. Biotechnol. 2017. [DOI]
N. Strohmeyer, M. Bharadwaj, M. Costell, R. Fässler, D. J. Müller “Fibronectin-bound α5β1 integrins sense load and signal to reinforce adhesion in less than a second“ Nat. Mater. 2017. [DOI]
Y. Toyoda, C. J. Cattin, M. P. Stewart, I. Poser, M. Theis, T. V. Kurzchalia, F. Buchholz, A. A. Hyman, D. J. Müller “Genome-scale single-cell mechanical phenotyping reveals disease-related genes involved in mitotic rounding“ Nat. Commun. 2017, 8(1):1266. [DOI]
D. Martínez-Martín, G. Fläschner, B. Gaub, S. Martin, R. Newton, C. Beerli, J. Mercer, C. Gerber, D. J. Müller “Inertial picobalance reveals fast mass fluctuations in mammalian cells“ Nature 2017, 550(7677):500-05. [DOI]
R. Newton, M. Delguste, M. Koehler, A. C. Dumitru, P. R. Laskowski, D. J. Müller, D. Alsteens “Combining confocal and atomic force microscopy to quantify single-virus binding to mammalian cell surfaces“ Nat. Protoc. 2017. [DOI]
P. R. Laskowski, M. Pfreundschuh, M. Stauffer, Z. Ucurum, D. FotiadisD. J. Müller “High-Resolution Imaging and Multiparametric Characterization of Native Membranes by Combining Confocal Microscopy and Atomic Force Microscopy-Based Multifunctional Toolbox“ ACS Nano 2017. [DOI]
N. Ritzmann, J. Thoma, S. Hirschi, D. Kalbermatter, D. FotiadisD. J. Müller “Fusion Domains Guide the Oriented Insertion of Light-Driven Proton Pumps into Liposomes“ Biophys J. 2017. [DOI]
T. Serdiuk, S. A. Mari, D. J. Müller “Pull-and-Paste of Single Transmembrane Proteins“ Nano Lett. 2017. [DOI]
M. Pfreundschuh, D. Harder, Z. Ucurum, D. FotiadisD. J. Müller “Detecting Ligand-Binding Events and Free Energy Landscape while Imaging Membrane Receptors at Subnanometer Resolution“ Nano Lett. 2017, 17(5):3261-69. [DOI]
Y. F. Dufrene, T. Ando, R. Garcia, D. Alsteens, D. Martinez-Martin, A. Engel, C. Gerber, D. J. Muller, D. J. Müller “Imaging modes of atomic force microscopy for application in molecular and cell biology“ Nat. Nanotechnol. 2017, 12(4):295-307. [DOI]
D. Alsteens, H. E. Gaub, R. Newton, M. Pfreundschuh, C. Gerber, D. J. Müller “Atomic force microscopy-based characterization and design of biointerfaces“ Nat. Rev. Mater. 2017, 2(5):17008. [DOI]
B. M. Gaub, D. J. Müller “Mechanical Stimulation of Piezo1 Receptors Depends on Extracellular Matrix Proteins and Directionality of Force“ Nano Lett. 2017, 17(3):2064-72
D. J. Müller, H. E. Gaub “Membrane proteins scrambling through a folding landscape“ Science 2017. [DOI]
M. Bharadwaj, N. Strohmeyer, G. P. Colo, J. Helenius, N. Beerenwinkel, H. B. Schiller, R. Fässler, D. J. Müller “αV-class integrins exert dual roles on α5β1 integrins to strengthen adhesion to fibronectin“ Nat. Commun. 2017. [DOI]
T. Serdiuk, D. Balasubramaniam, J. Sugihara, S. A. Mari, H. R. Kaback, D. J. Müller “YidC assists the stepwise and stochastic folding of membrane proteins“ Nat. Chem. Biol. 2016, 12:911-17. [DOI]
D. Alsteens, R. Newton, R. Schubert, D. Martinez-Martin, M. Delguste, B. RoskaD. J. Müller “Nanomechanical mapping of first binding steps of a virus to animal cells“ Nat. Nanotechnol. 2016:DOI:10.1038/nnano.2016.228. [DOI]
D. Harder, S. Hirschi, Z. Ucurum, R. Goers, W. Meier, D. J. MüllerD. Fotiadis “Engineering a Chemical Switch into the Light-driven Proton Pump Proteorhodopsin by Cysteine Mutagenesis and Thiol Modification“ Angew. Chem. Int. Ed.  2016, 55:8846. [DOI]
S. HirschiM. Stauffer, D. Harder, D. J. Müller, W. Meier, D. Fotiadis “Engineering and Assembly of Protein Modules into Functional Molecular Systems“ Chimia 2016, 6:398. [DOI]
T. Raschle, P. Rios Flores, C. Opitz, D. J. Müller, S. Hiller “Monitoring Backbone Hydrogen-Bond Formation in β-Barrel Membrane Protein Folding“ Angew. Chem. Int. Ed. 2016, 55:5952-55. [DOI]
L. Ge, S. Villinger, S. Mari, K. Giller, C. Griesinger, S. Becker, D. J. Müller, M. Zweckstetter “Molecular Plasticity of the Human Voltage-Dependent Anion Channel Embedded Into a Membrane“ Structure 2016, 24:585-94. [DOI]
M. Hilbert, A. Noga, D. Frey, V. Hamel, P. Guichard, S. H. Kraatz, M. Pfreundschuh, S. Hosner, I. Flückiger, R. Jaussi, M. M. Wieser, K. M. Thieltges, X. Deupi, D. J. Mülle, R. Kammerer, P. Gönczy, M. Hirono, M. O. Steinmetz, D. J. Müller “SAS-6 engineering reveals interdependence between cartwheel and microtubules in determining centriole architecture“ Nat. Cell Biol. 2016, 18:393. [DOI]
B. Source, C. Escobedo, Y. Toyoda, M. P. Stewart, C. J. Cattin, R. Newton, I. Banerjee, A. Stettler, B. Roska, S. Eaton, A. A. Hyman, A. Hierlemann, D. J. Müller “Mitotic cells contract actomyosin cortex and generate pressure to round against or escape epithelial confinement“ Nat. Commun. 2015, 6:8872. [DOI] [More Information]
M. Pfreundschuh, D. Alsteens, R. Wieneke, C. Zhang, S. R. Coughlin, R. Tampé, B. K. Kobilka, D. J. Müller “Identifying and quantifying two ligand-binding sites while imaging native human membrane receptors by AFM“ Nat. Commun. 2015, 6:8857. [DOI]
J. Thoma, B. M. Burmann, S. Hiller, D. J. Müller “Impact of holdase chaperones Skp and SurA on the folding of β-barrel outer-membrane proteins“ Nat. Struct. Mol. Biol. 2015, 22:795. [DOI] [More Information]
E. Mulvihill, K. van Pee, S. A. Mari, D. J. Müller, O. Yildiz “Directly Observing the Lipid-Dependent Self-Assembly and Pore-Forming Mechanism of the Cytolytic Toxin Listeriolysin O“ Nano Lett. 2015, 15:6965. [DOI]
C. J. Cattin, M. Düggelin, M. Martinez-Martin, D. C. Gerber, D. J. Müller, M. P. Stewart “Mechanical control of mitotic progression in single animal cells “ Proc. Natl. Acad. Sci. U.S.A. 2015, 112:11258. [DOI]
D. Alsteens, M. Pfreundschuh, C. Zhang, P. M. Spoerri, S. R. Coughlin, B. K. Kobilka, D. J. Müller “Imaging G protein–coupled receptors while quantifying their ligand-binding free-energy landscape“ Nat. Methods 2015, 12:845. [DOI] [Author File on Daniel J. Müller]
M. Yu, N. Strohmeyer, J. Wang, D. J. Müller, J. Helenius “Increasing throughput of AFM-based single cell adhesion measurements through multisubstrate surfaces“ Beilstein J. Nanotechnol. 2015, 6:157-66. [DOI]
R. Petrosyan, C. A. Bippes, S. Walheim, D. Harder, D. Fotiadis, T. Schimmel, D. Alsteens, D. J. Müller “Single-Molecule Force Spectroscopy of Membrane Proteins from Membranes Freely Spanning Across Nanoscopic Pores“ Nano Lett. 2015, 15:3624. [DOI]
T. Serdiuk, J. Sugihara, S. Mari, H. . Kaback, D. J. Müller “Observing a Lipid-Dependent Alteration in Single Lactose Permeases“ Structure 2015, 23:754-61. [DOI]
J. M. Nunes, M. Mayer-Hartl, F. U. Hartl, D. J. Müller “Action of the Hsp70 chaperone system observed with single proteins“ Nat. Commun. 2015, 6:6307. [DOI] [More Information]
D. Alsteens, S. Tay, D. J. Müller “Toward high-throughput biomechanical phenotyping of single molecules“ Nat. Methods 2015, 12:45. [DOI]