Voltage-gated K+-channels modulation by Ru-complexes

Many biological functions are regulated by the cellular membrane potential outer/inner voltage ratio. Amongst other ion channels, voltage-gated potassium channels (Kv) are one of the more abundant in biological membranes. A recent discovery shows that certain ruthenium containing compounds can influence, after activation by light, these channels, and thereby, the membrane potential. This proposal it is framed within the novel chemical-based approach in Optogenetics and it aims at understanding how these photo-activatable molecules can influence the opening or closing of the potassium channels. Using theoretical simulations the following scientific questions will be addressed: i) How does the substance penetrate the cell membrane ii) What are the photo- and electrochemical properties of the embedded compound iii) How does the underlying, membrane potential affecting molecular mechanism look like Contemporary computational methods will be used to carry out the simulations. Furthermore, the theoretical predictions will be validated by spectroscopic measurements. The outcome of this multidisciplinary approach will have a deep impact not only due to their biological relevance but also by helping the hosting group to broadening their methodological toolkit. The penetration of the ruthenium compound into the membrane will be simulated using classical molecular dynamics. The structures of stable conformers of the embedded substance get refined using a combination of classical and quantum mechanical methods. In particular, density functional theory will be used to describe the excited states of the organometallic compound. Finally, currently developed variants of molecular dynamics simulations will be used to simulate the conformational changes happening on a microsecond timescale. The calculations will be performed on the cluster of Prof. Leticia Gonzlezs group (University of Vienna) or on the Vienna Scientific Cluster (VSC). The spectroscopic measurements will be carried out in the laboratory of Prof. Peter Hegemann (Humboldt-University of Berlin) in cooperation with the group of Prof. Nuno Maulide (University of Vienna) where the synthesis of the organometallic compounds takes place. Finally, the aMD simulations will be performed in collaboration with the group of Dr. Carmen Domene (Kings College London, UK).

The main goal of this project was the understanding of how some small chemical compounds of ruthenium are able to, once added to light-insensitive cells, stimulate these cells upon illumination. In principle, once a photon targets one of these compounds, this ruthenium complex can donate or accept one electron from another chemical species in the surroundings (i.e. ascorbate). Since these ruthenium species are known to bind to the outer face of cell membranes, the oxidation/reduction process of many ruthenium compounds will change the polarization across the membrane, and additionally, will trigger the opening/closing of those ion channels located in the membrane that react to potential changes. In this project some ruthenium compounds and one voltage-gated potassium channel Kv have been simulated in the computer in the context of the cell membrane. In particular, with simplified molecular models, it has been investigated how these ruthenium compounds bind to the membrane, how light absorption changes the electronic distribution of these compounds, how the electron is transferred to another chemical species, and how the ion channel Kv senses the presence of the oxidized ruthenium species. As outcome, this work has provided rationale and tools for the design of novel ruthenium complexes. It establishes a solid foundation to tune the directionality of photoinduced processes in the field of Optogenetics.