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Nonlinear dynamics of selectivity, conductivity, and gating in biological ion channels

生物离子通道中选择性、电导率和门控的非线性动力学

基本信息

批准号：
EP/G070660/1
负责人：
Peter Vaughan Elsmere McClintock
金额：
$ 67.03万
依托单位：
Lancaster University
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2009
资助国家：
英国
起止时间：
2009 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FG070660%2F1
关键词：
Nonlinear dynamics selectivity conductivity gating

项目摘要

We propose to investigate the physics of biological ion channels. These natural conducting nanotubes control a vast range of biological functions. Analogous to nano-scale transistors, they are present in the membranes of all biological cells. Moving a finger involves the coordinated operation of billions of ion channels. Half of the metabolic energy consumed by the human brain is used by ion pumps moving K+ and Na+ in and out of nerve cells. Understanding ion channel structure and operation is not only relevant to curing disease, but may also pave the way to bio-computers and their integration with nano-electronics. Channels are extraordinarily complicated devices, built of thousands of atoms, flexible, and filled with ions and water dipoles that adjust their positions to movements of the ions and channel walls. They are very selective and sensitive to external conditions. E.g. the KcsA potassium channel discriminates between K+ and Na+ ions by a factor of 1000, even though they are of the same polarity and Na+ is actually smaller in diameter by 0.4A. Yet channels conduct up to 100 million ions/sec, i.e. almost at the rate of free diffusion, and display very robust performance. Modelling channels is a fundamentally difficult many-body problem with long range interactions and widely-varying timescales, ranging from sub-ps atomic motion to sub-ms gating dynamics. Despite impressive scientific progress, theoretical models of channels are often too simplistic to capture the all-important relationship between structure and function, e.g. traditional models of channel diffusion consider ions as point charges, water as continuous dielectric, and protein as a dielectric with rigid walls - although ion size, hydration, and interaction with protein vibrations in the pore are known to play crucial roles.Our main goal is to develop a novel Brownian dynamics (BD) description of channels by isolating biologically relevant degrees of freedom using molecular dynamics (MD), and to demonstrate theoretically and numerically that protein vibration, ion size and hydration at the selectivity filter, and charge fluctuations (all largely neglected in earlier work), provide leading order contributions to the channel's high conductivity and selectivity between ions of the same polarity. We now propose a full-scale research programme, building on the strong base of: (i) our EPSRC-funded (GR/S86174/01) preliminary project on BD simulations, Poisson-Nernst-Planck and reaction rate theories of ion channels; (ii) the Lancaster group's life-time expertise in non-equilibrium stochastic dynamics; (iii) their long-term collaboration with Rush University Medical College; and (iv) the international distinction and enormous experience of the Warwick group in MD simulation. We will seek a self-consistent explanation of how strong selectivity between alike ions can be combined with high conductivity, stress relaxation and energy dissipation in the channel by developing a novel approach based on a combination of BD and MD simulations. We will also try to establish how coupling to the ion permeation via vibrations of the protein walls changes the energetics and statistics of the gating. Our theoretical and simulation results will be compared with real potassium, calcium, and artificial channel data in collaboration with experimentalists in Oxford, Chicago, Chapel Hill and Groningen.The investigations bring new ideas from non-equilibrium physics to focus on long-standing problems that are of central importance in biology. The work will draw freely on the group's special expertise in nonlinear dynamics, fluctuation theory, coupled oscillators, and their biomedical applications. Even partial success in improving the understanding of conduction in open ion channels will be highly significant, and will more than justify the enterprise.

我们建议研究生物离子通道的物理性质。这些天然导电纳米管控制着广泛的生物功能。与纳米级晶体管类似，它们存在于所有生物细胞的膜中。手指的移动涉及数十亿离子通道的协调操作。人脑消耗的代谢能量的一半被离子泵用来将K+和Na+进出神经细胞。了解离子通道的结构和运作不仅与疾病的治疗有关，而且可能为生物计算机及其与纳米电子学的集成铺平道路。通道是非常复杂的装置，由数千个原子组成，具有灵活性，充满离子和水偶极子，它们可以根据离子和通道壁的运动调整位置。它们对外界条件非常挑剔和敏感。例如，KcsA钾离子通道区分K+和Na+离子的倍数是1000，尽管它们具有相同的极性，而且Na+的直径实际上比K+小0.4A。然而，通道传导高达1亿个离子/秒，即几乎以自由扩散的速度，并显示出非常强大的性能。通道建模是一个从根本上困难的多体问题，具有远距离相互作用和广泛变化的时间尺度，范围从亚ps原子运动到亚ms门控动力学。尽管取得了令人印象深刻的科学进步，但通道的理论模型往往过于简单，无法捕捉到结构和功能之间的重要关系，例如，传统的通道扩散模型认为离子是点电荷，水是连续的电介质，蛋白质是具有刚性壁的电介质——尽管已知离子大小、水合作用和孔中蛋白质振动的相互作用起着至关重要的作用。我们的主要目标是通过使用分子动力学（MD）分离生物学相关自由度来开发一种新的布朗动力学（BD）通道描述，并从理论上和数值上证明，选择性过滤器中的蛋白质振动、离子大小和水合作用以及电荷波动（在早期的工作中很大程度上被忽视）为通道的高电导率和相同极性离子之间的选择性提供了领先的贡献。我们现在提出一个全面的研究计划，建立在强大的基础上：(i)我们的epsrc资助（GR/S86174/01）的BD模拟，离子通道的泊松-能-普朗克和反应速率理论的初步项目；（ii）兰开斯特集团在非平衡随机动力学方面的终身专业知识；（三）与拉什大学医学院的长期合作；（iv）华威集团在MD模拟方面的国际声誉和丰富经验。我们将通过开发一种基于BD和MD模拟相结合的新方法，寻求一种自一致的解释，解释相似离子之间的强选择性如何与通道中的高电导率、应力松弛和能量耗散相结合。我们也将尝试建立耦合到离子渗透如何通过蛋白质壁的振动改变门控的能量学和统计。我们的理论和模拟结果将与牛津、芝加哥、教堂山和格罗宁根的实验人员合作，与真实的钾、钙和人工通道数据进行比较。这些研究带来了非平衡物理学的新思想，以关注生物学中长期存在的重要问题。这项工作将自由地利用该小组在非线性动力学、波动理论、耦合振荡器及其生物医学应用方面的特殊专业知识。即使在提高对开放离子通道传导的理解方面取得部分成功，也将是非常重要的，而且将比证明这项事业的合理性更有意义。