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

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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'.