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

我们建议研究生物离子通道的物理。这些天然的导电纳米管控制着广泛的生物功能。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。人类大脑消耗的一半代谢能量被离子泵用于将K+和Na+移入和移出神经细胞。了解离子通道的结构和操作不仅与治疗疾病有关，而且还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，灵活，充满离子和水偶极子，它们根据离子和通道壁的运动调整位置。他们对外界条件非常敏感和敏感。例如，KcsA钾通道以1000倍区分K+和Na+离子，即使它们具有相同的极性，并且Na+的直径实际上小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率传导，并且显示出非常稳健的性能。模拟通道是一个从根本上困难的多体问题，具有长距离相互作用和广泛变化的时间尺度，从亚ps原子运动到亚ms门控动力学。尽管科学进步令人印象深刻，但通道的理论模型往往过于简单，无法捕捉结构和功能之间的所有重要关系，例如，通道扩散的传统模型将离子视为点电荷，水视为连续电介质，蛋白质视为具有刚性壁的电介质-尽管离子大小，水合作用，我们的主要目标是发展一种新的布朗动力学（BD）描述的通道，通过使用分子动力学（MD）分离生物相关的自由度，并从理论上和数值上证明，蛋白质振动，离子大小和水合在选择性过滤器，和电荷波动（在早期的工作中很大程度上被忽略），提供领先的顺序贡献通道的高电导率和选择性之间的离子相同极性。我们现在建议一个全面的研究计划，建立在以下坚实的基础上：（i）我们的EPSRC资助（GR/S86174/01）关于BD模拟、Poisson-Nernst-Planck和离子通道反应速率理论的初步项目; ㈡兰开斯特小组在非平衡随机动力学方面的终生专门知识; ㈢他们与拉什大学医学院的长期合作;以及（iv）沃里克小组在MD模拟方面的国际声誉和丰富经验。我们将寻求一个自洽的解释如何强选择性之间的相似的离子可以结合高电导率，应力松弛和能量耗散的通道，通过开发一种新的方法的基础上结合BD和MD模拟。我们也将尝试建立如何耦合到离子渗透通过振动的蛋白质壁改变能量学和统计学的门控。我们的理论和模拟结果将与真实的钾，钙和人工通道数据进行比较，与牛津，芝加哥，查佩尔山和格罗宁根的实验学家合作。这项工作将自由借鉴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长。即使在提高对开放离子通道传导的理解方面取得了部分成功，也将具有非常重要的意义，并将大大证明企业的合理性。

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.