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Ionic Coulomb blockade oscillations and the physical origins of permeation, selectivity, and their mutation transformations in biological ion channels

离子库仑阻断振荡以及生物离子通道中渗透、选择性及其突变转化的物理起源

基本信息

批准号：
EP/M015831/1
负责人：
Peter Vaughan Elsmere McClintock
金额：
$ 100.11万
依托单位：
Lancaster University
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2015
资助国家：
英国
起止时间：
2015 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FM015831%2F1
关键词：
Ionic Coulomb blockade oscillations physical

项目摘要

We will apply physics to elucidate the operation of biological ion channels including the long-standing problem of how their function emerges from their structure. These natural nanotubes exist in the membranes of all biological cells. They control a vast range of biological functions and are crucially important for life. Just lifting a finger requires the coordinated operation of billions of ion channels. Understanding ion channels is relevant to curing many diseases, and may also provide the future basis for bio-computers and their integration with nano-electronics. The project promises significant contributions to the EPSRC Physics Grand Challenges (a) "Understanding the Physics of Life" and (b) "Emergence and Physics Far from Equilibrium" - and it has been inspired and encouraged by their associated NetworksPlus.Channels are extraordinarily complex devices, built of thousands of atoms, and operating under non-equilibrium conditions. They conduct selected ions discretely on "one-by-one" basis. Channels can be very selective, e.g. the calcium channel discriminates between Ca++ and Na+ ions by a factor of 1000, even though they are of almost identical size. Yet a channel conducts almost at the rate of free diffusion, like an open hole. Modelling channels is an innately difficult many-body problem with long range interactions and widely-varying timescales, ranging from ps atomic motion to ms gating dynamics. The detailed structures of some channels are now known, but this knowledge has helped much less than expected/hoped in understanding how they actually work.Our recent research has involved the analysis of a generic ion channel of very simple form: an open nanotube with some fixed charge around its middle, using both analytic theory and modelling with self-consistent electrostatic Brownian dynamics. We complemented this mesoscale description with molecular dynamics simulations that take account of individual atoms and provide the parameters needed by the analytic description. One outcome was our discovery of an emergent phenomenon: a periodic sequence of conduction-bands and stop-bands dependent on the fixed charge. We hypothesise that it is a manifestation of Ionic Coulomb blockade, closely analogous to Coulomb blockade oscillations in quantum dots. In the context of ion channels, this brings an entirely fresh vision of the conduction process. Our new model based on ionic Coulomb blockade seems potentially able to account for numerous earlier observations on wild-type channels and their mutants that have hitherto been regarded as mysterious and puzzling, bringing them together within a consistent, unified, picture. We now request the funding needed to exploit this scientific break-through. We will develop an analytic model of ionic Coulomb blockade oscillations, accounting for resonant fluctuation-induced permeation. We will validate the model through an experimental investigation of bacterial sodium channels and their mutants, comparing the measurements with model predictions, and seeking evidence for for Ca2+ and Ba2+ conduction bands, stop-bands and selectivity. By extending the ionic Coulomb blockade model to include the discreteness of the hydration shells around the ion, we can expect to account for selectivity between alike ions, i.e. of equal charge like Na+ and K+. From the perspective of our reduced model based on ionic Coulomb blockade, there is no inherent difference between an ion channel and an artificial charged nanopore. So we expect most of our results to be equally applicable to nanopores, if values of charge and dimensions are adjusted appropriately.The investigations bring ideas from far-from-equilibrium physics to bear on problems in biology that are also applicable to nanotechnology. The work will draw freely on the consortium's special expertise in experiments on ion channels, nonlinear dynamics, fluctuation theory, and molecular dynamics.

我们将应用物理学来阐明生物离子通道的运行，包括它们的功能如何从其结构中显现这一长期存在的问题。这些天然纳米管存在于所有生物细胞的膜中。它们控制着广泛的生物功能，对生命至关重要。仅仅动动一根手指就需要数十亿个离子通道的协调运行。了解离子通道与治愈许多疾病有关，也可能为生物计算机及其与纳米电子学的集成提供未来的基础。该项目承诺为EPSRC物理学大挑战(A)“理解生命的物理学”和(B)“浮现和远离平衡的物理”做出重大贡献-它受到了它们相关的NetworksPlus的启发和鼓励。通道是极其复杂的设备，由数千个原子组成，在非平衡条件下运行。他们在“一个接一个”的基础上谨慎地处理选定的离子。通道可能是非常选择性的，例如，钙通道区分钙离子和钠离子1000倍，即使它们的大小几乎相同。然而，渠道的传导几乎以自由扩散的速度进行，就像一个开放的洞。通道建模是一个复杂的多体问题，具有大范围的相互作用和变化很大的时间尺度，从ps原子运动到ms门控动力学。一些离子通道的详细结构现在已知，但这些知识对了解它们的实际工作原理的帮助远远低于预期/希望。我们最近的研究涉及到对一种非常简单的一般离子通道的分析：使用解析理论和自洽静电布朗动力学模型来分析一种中间有固定电荷的开放纳米管。我们用分子动力学模拟补充了这种中尺度描述，分子动力学模拟考虑了单个原子，并提供了解析描述所需的参数。一个结果是我们发现了一个紧急现象：依赖于固定电荷的导带和阻带的周期序列。我们假设它是离子库仑阻塞的一种表现，类似于量子点中的库仑阻塞振荡。在离子通道的背景下，这带来了对传导过程的全新看法。我们基于离子库仑阻塞的新模型似乎有可能解释许多早期对野生型通道及其突变体的观察，到目前为止，这些突变体一直被认为是神秘和令人费解的，将它们聚集在一幅一致的、统一的图景中。我们现在请求利用这一科学突破所需的资金。我们将建立一个离子库仑阻塞振荡的解析模型，该模型考虑了共振涨落诱导的渗透。我们将通过对细菌钠通道及其突变体的实验研究来验证该模型，将测量结果与模型预测进行比较，并寻找钙离子和Ba2+传导带、阻挡带和选择性的证据。通过扩展离子库仑阻塞模型，包括离子周围水化壳层的离散性，我们可以考虑类似离子之间的选择性，即像Na+和K+一样的相同电荷的离子。从我们基于离子库仑阻塞的简化模型的角度来看，离子通道和人工带电纳米孔之间没有本质上的区别。因此，我们预计，如果适当调整电荷和尺寸的值，我们的大多数结果将同样适用于纳米孔。研究将远离平衡的物理学的想法带到了也适用于纳米技术的生物学问题上。这项工作将自由地利用该联盟在离子通道、非线性动力学、涨落理论和分子动力学实验方面的特殊专业知识。