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学。这些天然导电纳米管控制着广泛的生物学功能。它们类似于纳米级晶体管，它们存在于所有生物细胞的膜中。移动手指涉及数十亿个离子通道的协调操作。人脑消耗的一半代谢能由离子泵移动K+和Na+进出神经细胞。了解离子通道的结构和操作不仅与固化疾病有关，而且还可能为生物计算机及其与纳米电子的整合铺平道路。通道是非常复杂的设备，由数千原子建造，柔性，并充满了离子和水偶极子，可将其位置调整为离子和通道墙的运动。它们对外部条件非常有选择性和敏感。例如。 KCSA钾通道将K+和Na+离子区分为1000倍，即使它们具有相同的极性，而Na+实际上在直径上较小。然而，频道的运行高达1亿离子/秒，即几乎以自由扩散的速度表现出非常强大的性能。建模通道是一个根本困难的多体问题，远距离相互作用和广泛不同的时间尺度，从子-PS原子运动到子-MS门控动力学。尽管科学进步令人印象深刻，但渠道的理论模型通常太简单了，无法捕获结构与功能之间的最重要关系，例如通道扩散的传统模型将离子视为点电荷，水作为连续的介电和蛋白质是具有刚性壁的介电 - 尽管已知离子大小，水分和与蛋白质振动的相互作用是众所周知，孔中的蛋白质振动是扮演至关重要的角色的。我们的主要目标是通过摩擦性的自由度（BD）的自由度来扮演至关重要的动力学（BD），以隔离型号的自由度（MD）的动力学来介绍（BD）。从理论和数字上讲，选择性过滤器处的蛋白质振动，离子尺寸和水合以及电荷波动（在早期工作中都大致忽略了），为通道的高电导率和相同极性离子之间的高电导率和选择性提供了领先的顺序贡献。现在，我们提出了一项全尺度研究计划，基于以下方面的强大基础：（i）我们的EPSRC资助（GR/S86174/01）BD模拟，Poisson-Nernst-Planck和ION频道的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；（iii）他们与拉什大学医学院的长期合作；（iv）MD模拟中沃里克集团的国际区别和巨大经验。我们将通过基于BD和MD模拟的组合开发一种新颖的方法来寻求如何将相似离子之间的强选择性与高电导率，压力松弛和能量耗散结合在一起的自洽解释。我们还将尝试通过蛋白质壁的振动来确定如何与离子渗透耦合改变门控的能量和统计。与牛津，芝加哥，芝加哥，教堂山和格罗宁根的实验者合作，我们的理论和仿真结果将与真实的钾，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，以关注长期存在的问题，这些问题在生物学中具有核心重要性。这项工作将自由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。即使是在改善开放离子渠道传导的理解方面的部分成功也将非常重要，并且将不仅仅证明企业是合理的。