University of Dundee

Professor Ulrich Zachariae

Computational Biophysics and Drug Discovery
Professor of Molecular Biophysics
Life Sciences Research Complex, University of Dundee, Dundee
Full Telephone: 
+44 (0) 1382 381261, int ext 81261


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. G Williamson, G Tamburrino, G Dias Mirandela, M Boeckstaens, M Bage, AV Pisliakov, CM Ives, E Terras, A Bizior, PA Hoskisson, AM Marini, U Zachariae*, A Javelle*: A two-lane mechanism for selective biological ammonium transport. *joint corresponding authors. eLife 9, e57183 (2020).

2. S Llabrés, MI Tsenkov, SA MacGowan, GJ Barton, U Zachariae: Disease related single point mutations alter the global dynamics of a tetratricopeptide (TPR) alpha-solenoid domain. J. Struct. Biol. 209, 107405 (2020).

3. I Rodriguez-Espigares, et al.: GPCRmd uncovers the dynamics of the 3D-GPCRome. Nature Methods 17, 777-787 (2020).

4. W Kopec, DA Köpfer, ON Vickery, A Bondarenko, TLC Jansen, BL de Groot, U Zachariae: Direct knock-on of desolvated ions governs strict ion selectivity in K+ channels. Nature Chemistry 10, 813-820 (2018).

5. ON Vickery, CA Carvalheda, S Zaidi, AV Pisliakov, V Katritch, U Zachariae: Intracellular transfer of Na+ in an active state G-protein coupled receptor. Structure 26, 171-180 (2018).

6. AWP Fitzpatrick, S Llabrés, A Neuberger, D Brook, XC Bai, S Murakami, U Okada, H van Veen, U Zachariae, SHW Scheres*, BF Luisi*, D Du*: Structure of a tripartite ABC drug efflux pump. Nature Microbiology 2, 17070 (2017).

7. C Kutzner, DA Köpfer, JP Machtens, BL de Groot, C Song, U Zachariae: Insights into the function of ion channels by Computational Electrophysiology simulations. Biochim. Biophys. Acta Biomembranes, 1858, 1741-1752 (2016).

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

9. DA Köpfer, C Song, T Gruene, GM Sheldrick, U Zachariae*, BL de Groot*: Ion permeation in K+ channels occurs by direct Coulomb knock-on. *joint corresponding authors. Science 346, 352-355 (2014).

10. C Song, C Weichbrodt, ES Salnikov, M Dynowski, BO Forsberg, B Bechinger, C Steinem, BL de Groot, U Zachariae*, K Zeth*: Crystal structure and functional mechanism of a human antimicrobial membrane channel. *joint corresponding authors. Proc. Natl. Acad. Sci. USA 110, 4586-4591 (2013)