Molecular modelling and simulations of membrane proteins

Principal Investigator: Jun.-Prof. Dr. Jan-Philipp Machtens (Head of Computational Neurophysiology Group, Institute of Complex Systems/ICS-4, Forschungszentrum Jülich)

We investigate structure–dynamics­–function relationships of membrane proteins involved in neuronal signaling using a combination of supercomputing, molecular simulations, machine learning, and biophysical experiments. Thereby, we aim at understanding essential physiological functions and changes in diseases at atomic resolution to advance identification of novel pharmacological targets.

Our methods include:

  • High-performance computing
  • Multiscale molecular modeling and simulations of proteins
  • Machine learning
  • Patch-clamp electrophysiology
  • Stopped-flow fluorescence spectroscopy

Currents projects:

  • Mechanisms and pharmacology of SLC1/EAAT glutamate transporters
  • Dysfunction of voltage-gated sodium channels in neuropathic pain syndromes
  • Function and regulation of SLC26 anion exchangers
  • Lipid and anion transport in TMEM16 scramblases
  • Gating mechanisms of P2X receptors (in collaboration with R Hausmann)
  • Simulation-based analysis of CYP450-enzyme variants in drug metabolism (in collaboration with J Stingl)

Selected publications:

Kortzak, D., Alleva, C., Weyand, I., Ewers, D., Franzen, A., Machtens, J.P.*, and Fahlke, Ch.* (2019) Allosteric gate modulation confers K+ coupling in glutamate transporters. EMBO J. 38, e101468. *shared last authorship

Bratanov, D., Kovalev, K., Machtens, J.P., Astashkin, R., Chizhov, I., Soloviov, D., Volkov, D., Polovinkin, V., Zabelskii, D., Mager, T., Gushchin, I., Rokitskaya, T., Antonenko, Y., Alekseev, A., Shevchenko, V., Yutin, N., Rosselli, R., Baeken, C., Borshchevskiy, V., Bourenkov, G., Popov, A., Balandin, T., Büldt, G., Manstein, D.J., Rodriguez-Valera, F., Fahlke, Ch., Bamberg, E., Koonin, E., and Gordeliy, V. (2019) Unique structure and function of viral rhodopsins. Nat. Commun. 10, 4939

Körner, J., Meents, J., Machtens, J.P., and Lampert, A. (2018) β1 subunit stabilises sodium channel Nav1.7 against mechanical stress. J. Physiol. 596, 2433–2445

Machtens, J.P., Briones, R., Alleva, C., de Groot, B.L., and Fahlke, Ch. (2017) Gating charge calculations by computational electrophysiology simulations. Biophys. J. 112, 1396–1405

Vickery, O. N., Machtens, J.P., Tamburrino, G., Seeliger, D. & Zachariae, U.    Structural Mechanisms of Voltage Sensing in G Protein-Coupled Receptors. Structure 24:997-1007 (2016).

Kutzner, C., Köpfer, D. A., Machtens, J.P., de Groot, B. L., Song, C. & Zachariae, U. (2016) Insights into the function of ion channels by computational electrophysiology simulations. Biochim. Biophys. Acta 1858:1741-1752

Fahlke, Ch., Kortzak, D. & Machtens, J.P. (2016) Molecular physiology of EAAT anion channels. Pflügers Arch 486, 491-502

Ewers, D., Becher, T., Machtens, J.P., Weyand, I., and Fahlke, Ch. (2013) Induced fit substrate binding to an archeal glutamate transporter homologue. Proc. Natl. Acad. Sci. USA 110, 12486-12491

Machtens, J.P., Kortzak, D., Lansche, C., Leinenweber, A., Kilian, P., Begemann, B., Zachariae, U., Ewers, D., de Groot, B.L., Briones, R., and Fahlke, Ch. (2015) Mechanisms of anion conduction by coupled glutamate transporters. Cell 160, 542-553