Effects of induced polarisation on nanoscale behaviour of water and ions in ion channel pores and biomimetic nanopores

生物离子通道通过允许离子和水选择性渗透穿过细胞膜以控制细胞电活动并维持细胞和离子稳态而对所有活细胞的健康功能是不可或缺的。由于离子通道功能障碍导致的疾病数量以及针对离子通道和相关蛋白活性的治疗药物的范围突出了它们的根本重要性。膜蛋白结构生物学的最新进展，如低温电子显微镜和基于神经网络模型的结构预测，导致通道结构被解决的数量接近指数增长。因此，需要对其功能进行准确的注释。因此，确定控制这些纳米级孔内渗透的分子机制对于理解其功能特性以及开发新的治疗策略和未来的药物发现至关重要。通道结构的计算模拟对于理解这些过程是必不可少的，因为它可以用于研究通道孔中的水和离子的行为，以深入了解它们在这种纳米空间中的行为。分子动力学（MD）模拟孔道具有很强的预测能力，已得到广泛的应用.这个博士项目将使用分子动力学模拟与极化和非极化力场1）研究阴离子选择性和结合自由能的离子载体和镊子，2）研究离子通道中的疏水门和诱导极化效应; 3）使用快速-一项提交给牛津大学BBSRC跨学科生物科学DTP的研究计划。这项工作是相关的BBSRC战略优先领域的“系统方法的生物科学”和“数据驱动的生物学”。

Biological ion channels are integral to the healthy function of all living cells by allowing the selective permeation of ions and water across cell membranes to control cellular electrical activity and maintain cellular and ionichomeostasis. Their fundamental importance is highlighted by the number of diseases that result from ion channel dysfunction, as well as the range of therapeutic drugs that target the activity of ion channels and related proteins.Recent advances in membrane protein structural biology such as cryogenic electron microscopy and structure prediction with neural network-based models result in near exponential growth in the number of channel structuresbeing solved. Hence accurate methods for their functional annotation are needed. Determining molecular mechanisms which control permeation within these nanometer-scale pores is therefore critical for understandingtheir functional properties as well as for the development of new therapeutic strategies and future drug discovery. Computational simulation of channel structures is essential to understand these processes as it can be used to studythe behaviour of water and ions in channel pores to provide insights into their behaviour in such nanoconned spaces. Molecular dynamics (MD) simulations of channel pores are now widely used and have powerful predictivecapabilities. This DPhil project will use MD simulations with polarizable and nonpolarizable force fields to 1) study anion selectivity and binding free energies of ion carriers and tweezers, 2) study hydrophobic gates and the effect ofinduced polarization in ion channels and 3) perform large scale channel annotation using a fast-growing database of newly resolved structures.A research proposal submitted for the BBSRC Interdisciplinary Bioscience DTP at the University of Oxford. This work is relevant to the BBSRC Strategic Priority Areas of 'Systems Approaches to the Biosciences' and 'DataDriven Biology'.