Single-channel Markov modelling of voltage-gated ion channels with simulations and implementation of the 2D-Fit algorithm on High Performance Computing Cluster

在这个项目中，我们希望探索HPC集群的计算能力，用马尔可夫模型来建模单通道膜片钳数据。具有时间序列模拟的2D-Dwell-Time拟合捕获具有高噪声背景的门控动力学，并且可以提取超出记录带宽的速率常数。这使得2D-Fit在将离子通道动力学与单分子模拟数据相关联方面具有特殊价值。此外，2D分布保持了连接状态的一致性。该算法能够提取出底层模型的全部复杂度，并区分不同的模型。借助HPC集群的计算能力，我们将能够严格测试算法并优化分析单通道时间序列的设置。此后，我们希望实现新的功能，以增加功率和算法的通用性。该项目的第二个重要目标是获取和模拟实验单通道膜片钳数据。我们希望了解β-分泌酶BACE 1与KCNQ家族离子通道的相互作用，以及蛋白酶如何在阿尔茨海默病（AD）的框架内改变门控的机制。2D-Fit程序将在GNU通用公共许可证（GNU GPL v3）下免费提供下载。这将有助于在短时间内提取完整和强大的门控模型，致力于了解离子通道的功能的研究。最后，我们想探讨的有用性的二维拟合分析其他数据从单离子通道和数据相关的光学单分子方法。

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.