University of Dundee

EASTBIO: Computational and experimental electrophysiology of eukaryotic and viral ion channels: (Professor U Zachariae; Dr S Pitt)

In electrically excitable cells such as neurons or muscle cells, ion channels enable electric signal transmission, for instance by electric action potentials or calcium release. In all other cell types, ion channels play key roles in forming the membrane potential and ensuring cellular ionic homeostasis. Even in viruses, ion channels perform essential functions during many stages of their infectious cycle such as virus entry and release from infected host cells. Ion channels are therefore highly important drug targets across a vast array of disease areas.

This project focuses on the function of the pharmaceutically important TRP superfamily of calcium channels and viral cation channels. By enhancing our understanding of how drugs modulate channel function, the results will aid drug design on this important class of target proteins.

By a combination of biomolecular simulations of ion channel structures, computational electrophysiology and patch-clamp/planar bilayer electrophysiology experiments we will investigate how TRP channels gate open and closed in response to various stimuli, transport ions, and interact with the ligands. In particular, we will study the determinants of drugs that intervene with these mechanisms to modulate channel function for therapeutic aims.

In electrically excitable cells such as neurons or muscle cells, ion channels enable electric signal transmission, for instance by electric action potentials or calcium release. In all other cell types, ion channels play key roles in forming the membrane potential and ensuring cellular ionic homeostasis. Even in viruses, ion channels perform essential functions during many stages of their infectious cycle such as virus entry and release from infected host cells. Ion channels are therefore highly important drug targets across a vast array of disease areas.

This project focuses on the function of the pharmaceutically important TRP superfamily of calcium channels and viral cation channels. By enhancing our understanding of how drugs modulate channel function, the results will aid drug design on this important class of target proteins.

By a combination of biomolecular simulations of ion channel structures, computational electrophysiology and patch-clamp/planar bilayer electrophysiology experiments we will investigate how TRP channels gate open and closed in response to various stimuli, transport ions, and interact with the ligands. In particular, we will study the determinants of drugs that intervene with these mechanisms to modulate channel function for therapeutic aims.

Further studies will address viral channels such as the SARS-Cov2 envelope protein, a sodium ion channel, and its inhibition by potential therapeutic drug molecules.

Intense training will be provided in biomolecular simulations, virtual drug screening, machine learning applied to computational drug design, as well as experimental electrophysiology techniques including patch-clamp and planar lipid bilayer recordings.

Further reading:

[1] Kopec W, Köpfer DA, Vickery ON, Bondarenko AS, Jansen TL, De Groot BL, Zachariae U. (2018). Direct knock-on of desolvated ions governs strict ion selectivity in K+ channels. Nature Chemistry 10(8):813-20.

[2] Mariano, G., Trunk, K., Williams, D. J., Monlezun, L., Strahl, H., Pitt, S. J. & Coulthurst, S. J. (2019). A family of Type VI secretion system effector proteins that form ion-selective pores. Nature Communications 10, 5484

Eligibility