We are interested in the functioning of molecular machines such as voltage-gated ion channels or Alzheimer’s Disease protease BACE1. Using patch-clamp recordings or time-resolved optical techniques, the behavior of single proteins is investigated. Subsequent Markov modelling of acquired time series using simulations or Deep Neural Networks provides insight into the molecular composition and function.
- Time Series Analysis
- HPC Simulations
- Deep Neural Networks
- Voltage-Gated Ion Channels
- Alzheimer’s Disease Protease BACE1
Single-channel Markov modelling of voltage-gated ion channels with simulations and implementation of the 2D-Fit algorithm on High Performance Computing Cluster
(Third Party Funds Single)Term: 1. April 2020 - 31. December 2023
Funding source: DFG-Einzelförderung / Sachbeihilfe (EIN-SBH)In this project, we want to explore the computational power of HPC-Cluster for modelling single-channel patch-clamp data with Markov models. The 2D-Dwell-Time fit with simulations of time series captures gating kinetics with a high background of noise and can extract rate constants beyond the recording bandwidth. That makes the 2D-Fit exceptional valuable for relating ion-channel kinetics with data from simulations of single molecules. In addition, 2D-distributions preserve the coherency of connected states. Thereby the algorithm can extract the full complexity of underlying models and distinguish different models. With the computing power of HPC-Cluster at hand we will be able to rigorous test the algorithm and optimize the settings for analysing single-channel time series. Thereafter we want to implement new features to increase the power and the versatility of the algorithm. The second important aim of the project is to acquire and model experimental single-channel patch-clamp data. We want to understand the interaction of β-secretase BACE1 with ion channels of the KCNQ family and the mechanisms how the protease alters gating in the framework of Alzheimer’s disease (AD).The 2D-Fit program will be made freely available for download under the GNU General Public License (GNU GPLv3). It will facilitate research dedicated to understanding the function of ion channels by extracting complete and robust gating models in short time. Finally, we want to probe the usefulness of the 2D-Fit to analyse other data from single ion channels and data related to optical single-molecule methods.
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- Thull, S., Neacsu, C., O'Reilly, A.O., Bothe, S., Hausmann, R., Huth, T.,... Lampert, A. (2020). Dataset of electrophysiological patch-clamp recordings of the effect of the compounds deltamethrin, ATx-II and β4-peptide on human cardiac Nav1.5 sodium channel gating properties. Data in Brief, 31. https://dx.doi.org/10.1016/j.dib.2020.105844
- Thull, S., Neacsu, C., O'Reilly, A.O., Bothe, S., Hausmann, R., Huth, T.,... Lampert, A. (2020). Mechanism underlying hooked resurgent-like tail currents induced by an insecticide in human cardiac Nav1.5. Toxicology and Applied Pharmacology, 397. https://dx.doi.org/10.1016/j.taap.2020.115010
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