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

激发极化对离子通道孔和仿生纳米孔中水和离子纳米级行为的影响

基本信息

批准号：
2446176
负责人：
金额：
--
依托单位：
University of Oxford
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=studentship-2446176
关键词：
Effects induced polarisation nanoscale behaviour

项目摘要

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'.

生物离子通道通过允许离子和水选择性渗透穿过细胞膜来控制细胞电活动并维持细胞和离子稳态，是所有活细胞健康功能不可或缺的一部分。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质活性的治疗药物的范围凸显了它们的根本重要性。膜蛋白结构生物学的最新进展，例如低温电子显微镜和基于神经网络模型的结构预测，导致正在解决的通道结构数量近乎指数级增长。因此需要准确的功能注释方法。因此，确定控制这些纳米级孔内渗透的分子机制对于了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至关重要，因为它可用于研究通道孔隙中水和离子的行为，以深入了解它们在此类纳米conned空间中的行为。通道孔隙的分子动力学（MD）模拟现已广泛应用，并具有强大的预测能力。该 DPhil 项目将使用可极化和不可极化力场的 MD 模拟来 1）研究离子载体和镊子的阴离子选择性和结合自由能，2）研究疏水门和离子通道中诱导极化的影响，3）使用快速增长的新解析结构数据库进行大规模通道注释。为 BBSRC 跨学科提交的研究提案牛津大学生物科学 DTP。这项工作与 BBSRC 的“生物科学系统方法”和“数据驱动生物学”战略优先领域相关。