Nanomechanical Functional Programming of Cellular and Synthetic Systems

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.


R. Goers, J. Thoma, N. Ritzmann, A. Di Silvestro, C. Alter, G. Gunkel-Grabole, D. FotiadisD. J. MüllerW. MeierOptimized reconstitution of membrane proteins into synthetic membranes“ Commun. Chem. (2018). [Link]
J. Thoma, Y. Sun, N. Ritzmann, D. J. MüllerPOTRA Domains, Extracellular Lid, and Membrane Composition Modulate the Conformational Stability of the β Barrel Assembly Factor BamA“ Structure (2018). [Link]
J. Thoma, S. Manioglu, D. Kalbermatter, P. D. Bosshart, D. FotiadisD. J. MüllerProtein-enriched outer membrane vesicles as a native platform for outer membrane protein studies“ Commun. Biol. (2018). [Link]
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. RoskaVirus stamping for targeted single-cell infection in vitro and in vivo“ Nat. Biotechnol. (2017). [Link]
N. Strohmeyer, M. Bharadwaj, M. Costell, R. Fässler, D. J. MüllerFibronectin-bound α5β1 integrins sense load and signal to reinforce adhesion in less than a second“ Nat. Mater. (2017). [Link]
Y. Toyoda, C. J. Cattin, M. P. Stewart, I. Poser, M. Theis, T. V. Kurzchalia, F. Buchholz, A. A. Hyman, D. J. MüllerGenome-scale single-cell mechanical phenotyping reveals disease-related genes involved in mitotic rounding“ Nat. Commun. 8, 1, 1266 (2017). [Link]
D. Martínez-Martín, G. Fläschner, B. Gaub, S. Martin, R. Newton, C. Beerli, J. Mercer, C. Gerber, D. J. MüllerInertial picobalance reveals fast mass fluctuations in mammalian cells“ Nature 550, 7677, 500-05 (2017). [Link]
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). [Link]
P. R. Laskowski, M. Pfreundschuh, M. Stauffer, Z. Ucurum, D. FotiadisD. J. MüllerHigh-Resolution Imaging and Multiparametric Characterization of Native Membranes by Combining Confocal Microscopy and Atomic Force Microscopy-Based Multifunctional Toolbox“ ACS Nano (2017). [Link]
N. Ritzmann, J. Thoma, S. Hirschi, D. Kalbermatter, D. FotiadisD. J. MüllerFusion Domains Guide the Oriented Insertion of Light-Driven Proton Pumps into Liposomes“ Biophys J. (2017). [Link]
T. Serdiuk, S. A. Mari, D. J. MüllerPull-and-Paste of Single Transmembrane Proteins“ Nano Lett. (2017). [Link]
M. Pfreundschuh, D. Harder, Z. Ucurum, D. FotiadisD. J. MüllerDetecting Ligand-Binding Events and Free Energy Landscape while Imaging Membrane Receptors at Subnanometer Resolution“ Nano Lett. 17, 5, 3261-69 (2017). [Link]
Y. F. Dufrene, T. Ando, R. Garcia, D. Alsteens, D. Martinez-Martin, A. Engel, C. Gerber, D. J. Muller, D. J. MüllerImaging modes of atomic force microscopy for application in molecular and cell biology“ Nat. Nanotechnol. 12, 4, 295-307 (2017). [Link]
D. Alsteens, H. E. Gaub, R. Newton, M. Pfreundschuh, C. Gerber, D. J. MüllerAtomic force microscopy-based characterization and design of biointerfaces“ Nat. Rev. Mater. 2, 5, 17008 (2017). [Link]
B. M. Gaub, D. J. MüllerMechanical Stimulation of Piezo1 Receptors Depends on Extracellular Matrix Proteins and Directionality of Force“ Nano Lett. 17, 3, 2064-72 (2017).
D. J. Müller, H. E. Gaub “Membrane proteins scrambling through a folding landscape“ Science (2017). [Link]
M. Bharadwaj, N. Strohmeyer, G. P. Colo, J. Helenius, N. Beerenwinkel, H. B. Schiller, R. Fässler, D. J. MüllerαV-class integrins exert dual roles on α5β1 integrins to strengthen adhesion to fibronectin“ Nat. Commun. (2017). [Link]
T. Serdiuk, D. Balasubramaniam, J. Sugihara, S. A. Mari, H. R. Kaback, D. J. MüllerYidC assists the stepwise and stochastic folding of membrane proteins“ Nat. Chem. Biol. 12, 911-17 (2016). [Link]
D. Alsteens, R. Newton, R. Schubert, D. Martinez-Martin, M. Delguste, B. RoskaD. J. MüllerNanomechanical mapping of first binding steps of a virus to animal cells“ Nat. Nanotechnol., DOI:10.1038/nnano.2016.228 (2016). [Link]
D. Harder, S. Hirschi, Z. Ucurum, R. Goers, W. MeierD. J. MüllerD. FotiadisEngineering a Chemical Switch into the Light-driven Proton Pump Proteorhodopsin by Cysteine Mutagenesis and Thiol Modification“ Angew. Chem. Int. Ed.  55, 8846 (2016). [Link]
S. HirschiM. Stauffer, D. Harder, D. J. MüllerW. MeierD. FotiadisEngineering and Assembly of Protein Modules into Functional Molecular Systems“ Chimia 6, 398 (2016). [Link]
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. 55, 5952-55 (2016). [Link]
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 24, 585-94 (2016). [Link]
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. MüllerSAS-6 engineering reveals interdependence between cartwheel and microtubules in determining centriole architecture“ Nat. Cell Biol. 18, 393 (2016). [Link]
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. MüllerMitotic cells contract actomyosin cortex and generate pressure to round against or escape epithelial confinement“ Nat. Commun. 6, 8872 (2015). [Link] [More Information]
M. Pfreundschuh, D. Alsteens, R. Wieneke, C. Zhang, S. R. Coughlin, R. Tampé, B. K. Kobilka, D. J. MüllerIdentifying and quantifying two ligand-binding sites while imaging native human membrane receptors by AFM“ Nat. Commun. 6, 8857 (2015). [Link]
J. Thoma, B. M. Burmann, S. Hiller, D. J. MüllerImpact of holdase chaperones Skp and SurA on the folding of β-barrel outer-membrane proteins“ Nat. Struct. Mol. Biol. 22, 795 (2015). [Link] [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. 15, 6965 (2015). [Link]
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. 112, 11258 (2015). [Link]
D. Alsteens, M. Pfreundschuh, C. Zhang, P. M. Spoerri, S. R. Coughlin, B. K. Kobilka, D. J. MüllerImaging G protein–coupled receptors while quantifying their ligand-binding free-energy landscape“ Nat. Methods 12, 845 (2015). [Link] [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. 6, 157-66 (2015). [Link]
R. Petrosyan, C. A. Bippes, S. Walheim, D. Harder, D. Fotiadis, T. Schimmel, D. Alsteens, D. J. MüllerSingle-Molecule Force Spectroscopy of Membrane Proteins from Membranes Freely Spanning Across Nanoscopic Pores“ Nano Lett. 15, 3624 (2015). [Link]
T. Serdiuk, J. Sugihara, S. Mari, H. . Kaback, D. J. MüllerObserving a Lipid-Dependent Alteration in Single Lactose Permeases“ Structure 23, 754-61 (2015). [Link]
J. M. Nunes, M. Mayer-Hartl, F. U. Hartl, D. J. MüllerAction of the Hsp70 chaperone system observed with single proteins“ Nat. Commun. 6, 6307 (2015). [Link] [More Information]
D. Alsteens, S. Tay, D. J. MüllerToward high-throughput biomechanical phenotyping of single molecules“ Nat. Methods 12, 45 (2015). [Link]

Project Leader

Daniel J. Müller

Persons involved

Benjamin Gaub


Molecular modules with new functionalities needed in a molecular factory will be designed and assembled in collaboration with projects led by Yaakov Benenson, Martin Fussenegger, Botond Roska, Wolfgang Meier, Dimitrios Fotiadis, Stefan Matile, Thomas R. Ward, Urs Dürig, Gebhard Schertler and Richard Kammerer.


Read more about the Müller-Group here.