Atomistic & Coarse-Grained Simulations of Proteins and Membranes
Proteins form the machinery of biological cells. To perform their actions, they must undergo conformational changes, much like the motions of macroscopic machines. These can be followed and studied by molecular dynamics simulations, which allow us to gain insight into the mechanisms by which they work - and the underlying energetic principles.
We apply and develop simulation methods on a range of length and time scales, especially focusing on membrane proteins and ion channels. Membrane-bound proteins form a large part of the proteome and control many of the cell's fundamental functions. To investigate ion channels, we have developed CompEl, "computational electrophysiology", which allows the prediction of channel ion conductance and selectivity based on electrochemical gradients. Of special interest to us are potassium channels, membrane pores formed by antimicrobial peptides (e.g., dermcidin), and pores in the outer membrane of bacteria that are found to be mutated in strains resistant to antibiotics (e.g., Neisserial PorB).
Movies of ion conduction across KcsA (first video) and dermcidin (second video) are shown below. In KcsA, potassium ions are shown as purple and pink spheres, while the protein is shown in green and water in red and white. In the second movie on dermcidin, the peptide aggregate is coloured blue and orange, and chloride ions are shown in red. The grey spheres depict lipid membrane head groups. We also investigate the molecular basis for the impressive elasticity of solenoid proteins, such as importin-beta and CRM1, and we have developed methods to quantify pattern formation in many-particle systems.
The movie is copyrighted by David A Köpfer
(Movie: Dr Chen Song)
1. O.N. Vickery, J.-P. Machtens, G. Tamburrino, D. Seeliger, U. Zachariae (2016). Structural mechanisms of voltage-sensing in G-protein coupled receptors. Structure, in press,
2. D.T. Baptista-Hon, A. Krah, U. Zachariae, T.G. Hales (2016). A role for loop G in the beta-1 strand in GABAA receptor activation. J. Physiol., in press,
3. Brandani, G. B., Schor, M., Morris, R., Stanley-Wall, N., MacPhee, C. E., Marenduzzo, D. and Zachariae, U. (2015) The Bacterial Hydrophobin BslA is a Switchable Ellipsoidal Janus Nanocolloid. Langmuir. 31, 11558-11563
4. Bromley, K. M., Morris, R. J., Hobley, L., Brandani, G., Gillespie, R. M., McCluskey, M., Zachariae, U., Marenduzzo, D., Stanley-Wall, N. R. and MacPhee, C. E. (2015) Interfacial self-assembly of a bacterial hydrophobin. Proceedings of the National Academy of Sciences of the United States of America. 112, 5419-5424
5. 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, C. (2015) Mechanisms of anion conduction by coupled glutamate transporters. Cell. 160, 542-553
6. Kopfer, D. A., Song, C., Gruene, T., Sheldrick, G. M., Zachariae, U.* and de Groot, B. L.* (2014) Ion permeation in K(+) channels occurs by direct Coulomb knock-on. Science. 346, 352-355
* Shared last authorship
7. C Song, C Weichbrodt, ES Salnikov, M Dynowski, BO Forsberg, B Bechinger, C Steinem, BL de Groot, U Zachariae *, K Zeth* (2013). Crystal structure and functional mechanism of a human antimicrobial membrane channel. Proc. Natl. Acad. Sci. USA 110 , 4586-4591.
* Joint corresponding/senior authorship
8. U Zachariae, R Schneider, R Briones, Z Gattin, JP Demers, E Maier, M Zweckstetter, C
Griesinger, S Becker, R Benz, BL de Groot, A Lange (2012)
Beta-barrel mobility underlies closure of the voltage-dependent anion channel.
Structure 20, 1540-1549.
9. C Kutzner, H Grubmüller, BL de Groot, U Zachariae (2011)
Computational electrophysiology: The molecular dynamics of ion channel permeation and selectivity in atomistic detail. Biophys.J. , 101, 809-817.
10. C Kappel, U Zachariae , N Dölker, H Grubmüller (2010) An unusual hydrophobic core confers extreme flexibility to HEAT repeat proteins. Biophys. J. 99 , 1596-1603.