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Molecular Dynamics Study of Voltage-Gated Sodium/Potassium Channels Daniel Bauer and Prof

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Molecular Dynamics Study of Voltage-Gated Sodium/Potassium Channels Daniel Bauer and Prof Project Manager Molecular Dynamics Study of Daniel Bauer voltage-gated Sodium/Potassium Principal Investigator channels Prof. Dr. Kay Hamacher Project Term Daniel Bauer and Prof. Dr. Kay Hamacher 2018 - 2019 Clusters Lichtenberg Cluster Darmstadt Software GROMACS Additional Software PLUMED, APBS, MODELLER Institute Computational Biology and Simulation University Technische Universität Darmstadt Figure 1: The sodium/potassium channel HCN1 embedded into a membrane bilayer. HCN1 is shown as green cartoon, membrane as balls and sticks and ions as purple/green spheres. The blue surface represents water. Introduction Ion channels play a fundamental key role in all living organisms and are crucial for the signal transduction of neurons in higher animals. In human, the hyperpolarization-activated cyclicnucleotide-gated (HCN) sodium/potassium channels of the HCN family are crucial for various biological processes. In the neural and cardiovascular system, they are responsible for the pacemaker current (also known as funny current If), which is characterized by a slow and rhythmic mixed sodium and potassium influx into cells. Mutations in the genes of the HCN family have been linked to various diseases, including rhythmias, epilepsies and neuropathic pain.[1] Even though discovered several decades ago, only little is known about why HCN channels act so different compares to their relatives (potassium selective channels). However, the recently printed 04. Oct 2021 - 21:58 https://www.hkhlr.de/projects/1689 page 1 of 3 Molecular Dynamics Study of voltage-gated Sodium/Potassium channels Daniel Bauer and Prof. Dr. Kay Hamacher revealed 3D structure of one member of this family — HCN1 — allows us to use computational simulation techniques to investigate some of the key aspects of these channels: HCN channelsare only weakly potassium selective and they activate at hyperpolarizing voltages.[2] Methods We use MD simulations of protein/membrane systems to simulate potassium channels embedded into membrane systems. In this simulation method, the physical movement of atoms is solved using Newton’s equations of motion to approximate the dynamic evolution of the system. This is combined with enhanced sampling techniques to sample states that are usually not accessible by classical MD simulation as well as novel analysis tools.[3, 4, 5] Results Our latest studies focussed on the effects of mutations on the HCN1 channel structure and why specific mutations are linked to epilepsy. In combination with in-vitro experiments, we were able to show that mutation of a glycine residue in the central pore of HCN1 can stop the channel from closing but also blocks ion conduction. Therefore, we have been able to give a plausible explanation to the question why mutations of this residue are linked to severe forms of epileptic encephalopathy in human. Outlook In the future, we plan to use our mutation modelling and simulation pipeline to investigate the role of key residues of HCN channels for channel function. In this context we hope to gain insight into the mechanism of voltage-dependent gating in this new class of ion channels. Additionally, we plan to investigate the ion selectivity of HCN channels in comparision to their more selective relatives. Reference [1] O. Postea and M. Biel. Exploring HCN channels as novel drug targets. Nature ReviewsDrug Discovery, 10(12):903{914, Nov. 2011. issn: 1474-1776. doi: 10.1038/nrd3576. http://www.nature.com/doifinder/10.1038/nrd3576 [2] C.-H. Lee and R. MacKinnon. Structures of the Human HCN1 Hyperpolarization-ActivatedChannel. Cell, 168(1-2):111{120.e11, Jan. 2017. issn: 00928674. doi: 10.1016/j.cell.2016.12.023. http://linkinghub.elsevier.com/retrieve/pii/S0092867416317391%20https ://linkinghub.elsevier.com/retrieve/pii/S0092867416317391 [3] D. Van Der Spoel, E. Lindahl, B. Hess, G. Groenhof, A. E. Mark, and H. J. C. Berendsen.GROMACS: Fast,exible, and free. Journal of Computational Chemistry, 26(16):1701{1718,Dec. 2005. issn: 0192-8651. doi: 10.1002/jcc.20291. http://www.ncbi.nlm.nih.gov/pubmed/16211538%20http://doi.wiley.com/ 10.1002/jcc.20291 [4] G. A. Tribello, M. Bonomi, D. Branduardi, C. Camilloni, and G. Bussi. printed 04. Oct 2021 - 21:58 https://www.hkhlr.de/projects/1689 page 2 of 3 Molecular Dynamics Study of voltage-gated Sodium/Potassium channels Daniel Bauer and Prof. Dr. Kay Hamacher PLUMED 2: New feathers for an old bird, Oct. 2013. doi: 10.1016/j.cpc.2013.09.018. arXiv: 1310.0980. https://arxiv.org/pdf/1310.0980.pdf%20http://arxiv.org/abs/1310.0980% 20http://dx.doi.org/10.1016/j.cpc.2013.09.018 [5] P. Kunzmann and K. Hamacher. Biotite: a unifying open source computational biology framework in Python. BMC Bioinformatics, 19(1):346, Dec. 2018. issn: 1471-2105. doi: 10.1186/s12859-018-2367-z. https://bmcbioinformatics.biomedcentral.com/ articles/10.1186/s12859-018-2367-z [6] C. Marini, A. Porro, A. Rastetter, C. Dalle, I. Rivolta, D. Bauer, R. Oegema, C. Nava, E.Parrini, D. Mei, C. Mercer, R. Dhamija, C. Chambers, C. Coubes, J. Thévenon, P. Kuentz,S. Julia, L. Pasquier, C. Dubourg, W. Carré, A. Rosati, F. Melani, T. Pisano, M. Giardino, A. M. Innes, Y. Alembik, S. Scheidecker, M. Santos, S. Figueiroa, C. Garrido, C. Fusco, D. Frattini, C. Spagnoli, A. Binda, T. Granata, F. Ragona, E. Freri, S. Franceschetti, L. Canafoglia, B. Castellotti, C. Gellera, R. Milanesi, M. M. Mancardi, D. R. Clark, F. Kok, K. L. Helbig, S. Ichikawa, L. Sadler, J. Neupauerovà, P. Laššuthova, K. Ŝtěrbovà, A. Laridon, E. Brilstra, B. Koeleman, J. R. Lemke, F. Zara, P. Striano, J. Soblet, G. Smits, N. Deconinck, A. Barbuti, D. DiFrancesco, E. LeGuern, R. Guerrini, B. Santoro, K. Hamacher, G. Thiel, A. Moroni, J. C. DiFrancesco, and C. Depienne. HCN1 mutation spectrum: from neonatalepileptic encephalopathy to benign generalized epilepsy and beyond. Brain, 141(11):3160{3178, Nov. 2018. doi: 10.1093/brain/awy263. http://www.ncbi.nlm.nih.gov/pubmed/30351409 Last Update: 2021-05-21 14:56 printed 04. Oct 2021 - 21:58 https://www.hkhlr.de/projects/1689 page 3 of 3 Powered by TCPDF (www.tcpdf.org).
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