On the importance of atomic fluctuations, protein flexibility, and solvent in ion permeation.
On the importance of atomic fluctuations, protein flexibility, and solvent in ion permeation.
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DOI：
10.1085/jgp.200409111
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发表时间：
2004-12
影响因子：
3.8
通讯作者：
Roux, Benoit
中科院分区：
文献类型：
--
作者：
Allen, Toby W;Andersen, O S;Roux, Benoit
蛋白质，包括离子通道，通常被描述为一些平均结构，并被描绘为浸入无特征溶剂连续体中的刚性实体。这种简化的观点，它提供了一个方便的蛋白质的整体结构的表示，招致的风险，不强调重要的功能蛋白质的基础，如热波动的原子位置和离散的溶剂分子。这些因素变得特别重要的情况下，离子运动通过窄孔，其中的热波动的幅度可以是可比的离子孔原子分离，使得离子通道相互作用的强度可以显着变化的离子和周围的蛋白质和孔隙水的瞬时配置的函数。描述离子渗透通过狭窄的孔隙，采用静态蛋白质结构和宏观连续介质溶剂，因此面临根本的困难。我们使用基于短杆菌肽A和KcsA钾通道的简单模型计算来说明这一点，该模型显示热原子波动导致能量分布变化数十千卡/摩尔。因此，在刚性孔模型的框架内，离子通道能量学对实验结构的选择以及如何分配空间依赖性介电常数非常敏感。鉴于这些观察结果，任何基于刚性结构的描述的意义似乎都是有限的。从一个单一的结构创建一个导电通道模型需要大量的和任意的工程模型参数，使得它难以为这样的方法，以帮助我们理解离子渗透在微观水平。
Proteins, including ion channels, often are described in terms of some average structure and pictured as rigid entities immersed in a featureless solvent continuum. This simplified view, which provides for a convenient representation of the protein's overall structure, incurs the risk of deemphasizing important features underlying protein function, such as thermal fluctuations in the atom positions and the discreteness of the solvent molecules. These factors become particularly important in the case of ion movement through narrow pores, where the magnitude of the thermal fluctuations may be comparable to the ion pore atom separations, such that the strength of the ion channel interactions may vary dramatically as a function of the instantaneous configuration of the ion and the surrounding protein and pore water. Descriptions of ion permeation through narrow pores, which employ static protein structures and a macroscopic continuum dielectric solvent, thus face fundamental difficulties. We illustrate this using simple model calculations based on the gramicidin A and KcsA potassium channels, which show that thermal atomic fluctuations lead to energy profiles that vary by tens of kcal/mol. Consequently, within the framework of a rigid pore model, ion-channel energetics is extremely sensitive to the choice of experimental structure and how the space-dependent dielectric constant is assigned. Given these observations, the significance of any description based on a rigid structure appears limited. Creating a conducting channel model from one single structure requires substantial and arbitrary engineering of the model parameters, making it difficult for such approaches to contribute to our understanding of ion permeation at a microscopic level.