Molecular modeling of ion channels

(Foto: Anna Weinzinger)

We use computational methods (including homology modelling, molecular dynamics simulations, docking investigations etc.) to explore the relationship between structure, function and dynamics of ion channels. We currently focus on several distinct ion channel families including K+, Ca2+ and Nav channels. The recent breakthrough in x-ray crystallography and cryo-electron-microscopy, enables detailed insights into the three-dimensional architecture of more and more of these channels, allowing detailed insights into their structure. Although, there is an increasing amount of structural information available, many questions, particular concerning the dynamics associated with gating, selectivity, conductance and ligand binding remain unanswered. Computer simulations allow us to simulate the motions of these proteins and to explore the relationship between (static) structure and dynamic function.

Our main research questions are (i) to understand how ion channels are gated (ii) how they are regulated by physiological ligands, (iii) how inherited gain-or loss-of-function mutations affect normal function, and (iv) how small molecule modulation affects channel action (including off-target effects). Our multi-disciplinary ranges from state-of-the-art in silico methods such as molecular dynamics simulations, enhanced sampling techniques, free energy calculations and computational electrophysiology and in close collaboration with experimental labs we perform (bio)chemical, pharmacological and biophysical studies, which enable us to unravel the inner workings of ion channels.

(Foto: Michael Bründl)

Selected publications:

Chen, X, Garon, A, Wieder, M, Houtman, MJC, Zangerl-Plessl, EM, Langer, T, van der Heyden, MAG, Stary-Weinzinger, A. (2019) Computational identification of novel Kir6 channel inhibitors. Front. Pharmacol. in press https://doi: 10.3389/fphar.2019.00549

In this project we developed a novel computational strategy to screen for new uses of approved drugs. This is particularly useful for development of drug-based therapies for ultra-rare diseases such as Cantú Syndrome.

Dierich, M, van Ham, W.B., Stary-Weinzinger, A, Leitner M.G. (2019) Histidine at determines the low quinine sensitivity of ether-à-go-go (Eag) channel superfamily member Kv12.1. Br J Pharmacol. in press https://doi: 10.1111/bph.14693

This study highlights the functional and pharmacological diversity of the EAG superfamily.

Houtman, M, Chen, X, Quile, M, Duran, K, van Haaften, G, Stary-Weinzinger, A, van der Heyden, M.A.G. (2019) Glibenclamide and HMR1098 normalize Cantú Syndrome-associated gain-of-function currents. J Cell and Mol Med. in press

This collaborative work with Marcel van der Heyden from the University of Utrecht reveals that Cantú syndrome-associated gain-of-function currents can be normalized by applying existing drugs, albeit at supraclinical drug concentrations only.

a complete list of publicatons can be found here 

Preprints:

Hellsberg, E, Ecker, GF, Stary-Weinzinger, A, Forrest LR. (2019) A structural model of the human serotonin transporter in an outward-occludedstate. https://www.biorxiv.org/content/10.1101/637009v1

Zangerl-Plessl, EM*, Lee SJ*, Maksaev, G, Bernsteiner, H, Ren, F, Yuan, P, Stary-Weinzinger, A#, Nichols, CG#. (2019) Atomistic basis of opening and conduction in mammalian inward rectifier potassium (Kir2.2) channels. https://www.biorxiv.org/content/10.1101/642090v1

Current Funding:

  1. FWF doctoral program "Molecular Drug Targets" grant W1232, 2010 - 2023

  2. e-rare2: "Sulfonylurea to treat Cantú syndrome",  2015 - 2019, FWF

Current group members:

  • Anna Weinzinger (Group leader)
  • Eva-Maria Plessl (Zangerl) (Postdoc, shared with Prof. Hering)
  • Harald Bernsteiner (MolTag PhD student)
  • Xingyu Chen (MolTag PhD student)
  • Michael Bründl (MolTag PhD student)
  • Eva Hellsberg (MolTag PhD student, Ecker group, 1 year internship)
  • Milica Gacesa (master student)
  • Theres Friesacher (master student)
  • Niko Schramböck (master student)
  • Nabil Mohamed (master student)
  • Simone Strohmaier (bachelor student)
  • Sarala Pellikan (PhD student)

Former group members:

  • Dina Mohamed (master student)
  • Ines Brammer (master student)
  • Willem B. van Ham (6 month exchange student, University of Utrecht)
  • Marielle Mattle (bachelor student)
  • Hristiyana Tatarova (Erasmus student, King's College London)
  • Michael Derflinger (master student)
  • Michael Bründl (master student)
  • Panisak Boonamnaj (ASEA-NET exchange student, TH)
  • Milica Skenderovic (master student)
  • Mona Abdelghani (visiting student, EG)
  • Song Ke (MolTag PhD student)
  • Tobias Linder (MolTag PhD student)
  • Kirsten Knape (PhD student, co-supervision with Peter Wolschann)