Exploring the origin of the ion selectivity of the KcsA potassium channel
Exploring the origin of the ion selectivity of the KcsA potassium channel
复制标题
DOI：
10.1002/prot.10455
复制
发表时间：
2003-08-15
影响因子：
2.9
通讯作者：
Warshel, A
中科院分区：
文献类型：
--
作者：
Burykin, A;Kato, M;Warshel, A
关于生物离子通道的结构信息的可用性提供了一个机会，以获得详细的了解生物系统的离子选择性的控制。然而，通过计算机模拟方法来完成这一任务是非常具有挑战性的。首先，虽然离子输运的激活势垒可以通过微观模拟来评估，但是通过这种方法很难获得准确的结果。第二，选择性与实际离子电流有关，而不直接与单个激活势垒有关。因此，它是必不可少的，以模拟离子电流，这是目前无法完成的微观MD方法。为了应对这一挑战，我们开发并改进了一种能够评估离子电流的方法，同时仍然反映了给定通道的现实特征。我们的方法涉及产生半宏观自由能表面的通道/离子系统和布朗动力学（BD）模拟相应的离子电流。与大多数替代宏观模型相比，我们的方法能够再现不同离子的自由能表面之间的差异，从而解决选择性问题。我们的方法是用于对K+和Na+离子的KcsA通道的选择性的研究。BD模拟与计算的自由能分布产生了可观的选择性。据我们所知，这是第一次在离子电流的选择性的趋势是由计算机模拟方法产生的。然而，计算的选择性仍然小于其实验估计。认识到计算的配置文件是不完美的，我们研究如何在这些配置文件中的变化可以解释所观察到的选择性。据发现，起源的选择性是更复杂的比一般假设。观察到的选择性可以通过增加选择性过滤器的出口和入口处的势垒来再现，但是势垒的必要变化接近PDLD/S-LRA计算中的误差极限。还考虑了可以增加选择性的其他选择，包括Na+和Na+之间的差异。Na+和K+ K+相互作用。然而，这种有趣的效果似乎不会导致选择性的重大差异，因为在强相互作用的极限下，Na+离子倾向于以比K+离子更不协调的方式移动。在不同结合位点处的相对结合能的变化在改变选择性方面也不是那么有效。最后，它指出，使用计算的配置文件作为起点，并迫使模型，以满足不同的实验为基础的约束，最终应该提供更详细的了解不同的复杂因素，涉及生物通道的离子选择性。(C)2003 Wiley-Liss，Inc.
The availability of structural information about biological ion channels provides an opportunity to gain a detailed understanding of the control of ion selectivity by biological systems. However, accomplishing this task by computer simulation approaches is very challenging. First, although the activation barriers for ion transport can be evaluated by microscopic simulations, it is hard to obtain accurate results by such approaches. Second, the selectivity is related to the actual ion current and not directly to the individual activation barriers. Thus, it is essential to simulate the ion currents and this cannot be accomplished at present by microscopic MD approaches. In order to address this challenge, we developed and refined an approach capable of evaluating ion current while still reflecting the realistic features of the given channel. Our method involves generation of semimacroscopic free energy surfaces for the channel/ions system and Brownian dynamics (BD) simulations of the corresponding ion current. In contrast to most alternative macroscopic models, our approach is able to reproduce the difference between the free energy surfaces of different ions and thus to address the selectivity problem. Our method is used in a study of the selectivity of the KcsA channel toward the K+ and Na+ ions. The BD simulations with the calculated free energy profiles produce an appreciable selectivity. To the best of our knowledge, this is the first time that the trend in the selectivity in the ion current is produced by a computer simulation approach. Nevertheless, the calculated selectivity is still smaller than its experimental estimate. Recognizing that the calculated profiles are not perfect, we examine how changes in these profiles can account for the observed selectivity. It is found that the origin of the selectivity is more complex than generally assumed. The observed selectivity can be reproduced by increasing the barrier at the exit and the entrance of the selectivity filter, but the necessary changes in the barrier approach the limit of the error in the PDLD/S-LRA calculations. Other options that can increase the selectivity are also considered, including the difference between the Na+...Na+ and K+...K+ interaction. However, this interesting effect does not appear to lead to a major difference in selectivity since the Na+ ions at the limit of strong interaction tend to move in a less concerted way than the K+ ions. Changes in the relative binding energies at the different binding sites are also not so effective in changing the selectivity. Finally, it is pointed out that using the calculated profiles as a starting point and forcing the model to satisfy different experimentally based constraints, should eventually provide more detailed understanding of the different complex factors involved in ion selectivity of biological channels. (C) 2003 Wiley-Liss, Inc.