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Through the Channel and around the Channel: Validating and Comparing Microscopic Approaches for Evaluation of Free Energy Profiles for Ion Penetration through Ion Channels

机译：通过通道和通道周围：验证和比较用于评估通过离子通道进行离子渗透的自由能分布的微观方法

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摘要

Microscopic calculations of free energy profiles for ion transport through biological ion channels presents a very serious challenge to modern simulation approaches. The main problem is due to the major convergence problems associated with the heterogeneous landscape of the electrostatic environment in ion channels and with the need to evaluate the profile associated with the transfer of the ion from bulk water to the channel environment. This problem is compounded by the lack of reliable and relevant benchmarks that can discriminate between alternative approaches. The present study is aimed at reducing the above problems by defining benchmarks that are directly relevant to ion channels and can also give converging results. This is done by constructing a series of models of a truncated gramicidin channel with different numbers of water molecules and by comparing the profiles for going around the channel and through the channel. These discriminating models are then used to validate and compare the adiabatic charging free energy perturbation (FEP) approach combined with an umbrella sampling approach (Warshel J. Phys. Chem., 86, 2218,>1982) and the potential of mean force (PMF) approach used frequently in studies of ion channels. It is found that both approaches work quite well until one moves to the fully solvated channel case. In this limit the PMF approach starts to give different results for the overall work of going through the channel and around the channel while the FEP approach gives physically consistent results. The present benchmark also indicates that the weighted histogram analysis method (WHAM) approach does not offer a significant advantage over earlier approaches at least as much as studies of ion channels are concerned. Finally, it is concluded that the FEP approach may be more useful in evaluating the overall barrier for moving ions from water to ion channels and that in some cases it might be beneficial to use the FEP approach for selective points along the channel and then to connect these points by PMF calculations.
机译：通过生物离子通道传输离子的自由能曲线的微观计算对现代模拟方法提出了非常严峻的挑战。主要问题是由于与离子通道中静电环境的异质性景观相关的主要收敛问题，以及需要评估与离子从大量水向通道环境的转移相关的轮廓所引起的。由于缺乏可区分其他方法的可靠且相关的基准，这个问题变得更加复杂。本研究旨在通过定义与离子通道直接相关的基准来减少上述问题，并且还可以得出收敛的结果。这是通过构建截短的短杆菌肽通道的一系列具有不同数量水分子的模型并通过比较通道周围和通道中的分布图来完成的。然后，这些区分模型用于验证和比较绝热带电自由能扰动（FEP）方法与伞式采样方法（Warshel J. Phys。Chem。，86，2218，> 1982 ）和在离子通道研究中经常使用的平均力（PMF）方法的潜力。发现在进入完全溶剂化的通道情况之前，两种方法都可以很好地工作。在此限制下，PMF方法开始为通过通道和通道周围的整体工作提供不同的结果，而FEP方法则提供物理上一致的结果。本基准还表明，加权直方图分析方法（WHAM）的方法与早期方法相比，至少在涉及离子通道研究方面没有提供明显的优势。最后，得出的结论是，FEP方法可能在评估将离子从水移动到离子通道的整体障碍方面更有用，并且在某些情况下，使用FEP方法沿通道的选择点然后进行连接可能会有所帮助这些点是通过PMF计算得出的。

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    Mitsunori Kato; Arieh Warshel;

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  • 年(卷),期 -1(109),41
  • 年度 -1
  • 页码 19516–19522
  • 总页数 19
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