Full kinetics of CO entry, internal diffusion, and exit in myoglobin from transition-path theory simulations.
Full kinetics of CO entry, internal diffusion, and exit in myoglobin from transition-path theory simulations.
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DOI：
10.1021/ja512484q
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发表时间：
2015-03-04
影响因子：
15
通讯作者：
Abrams CF
中科院分区：
文献类型：
--
作者：
Yu TQ;Lapelosa M;Vanden-Eijnden E;Abrams CF
我们使用马尔可夫里程碑式的分子动力学（MD）模拟的集体变量空间的棋盘格的CO定位在肌红蛋白估计的动力学的入口，出口，和内部的网站跳跃。通过使用过渡路径理论（TPT）分析该空间中的自由能表面来确定镶嵌，该过渡路径理论提供了用于定义最佳里程碑的标准，允许短的、独立的、单元格约束的MD模拟以提供适当加权的动力学数据。我们粗粒产生的动力学模型在两个层面上：第一，使用晶体学相关的内部空腔和它们的预测互连和溶剂门户网站;第二，作为一个三态侧路径计划的灵感来自于类似的模型从成对重组实验。我们显示半定量协议与实验上的入口和出口率，并在识别的所谓的“组氨酸门”的位置64通过溶剂和远端口袋之间的流量的90%通过。我们还表明，与六维计算，通过组氨酸门逃逸的最小自由能的途径是一个“敲门”的机制，其中配体和门的运动是顺序和相互依赖的。总之，这些结果表明，这样的TPT模拟确实是一个很有前途的方法，以克服MD的实际时间尺度的限制，允许可靠的估计过渡机制和亚稳态之间的速率。
We use Markovian milestoning molecular dynamics (MD) simulations on a tessellation of the collective variable space for CO localization in myoglobin to estimate the kinetics of entry, exit, and internal site-hopping. The tessellation is determined by analysis of the free-energy surface in that space using transition-path theory (TPT), which provides criteria for defining optimal milestones, allowing short, independent, cell-constrained MD simulations to provide properly weighted kinetic data. We coarse grain the resulting kinetic model at two levels: first, using crystallographically relevant internal cavities and their predicted interconnections and solvent portals; and second, as a three-state side-path scheme inspired by similar models developed from geminate recombination experiments. We show semiquantitative agreement with experiment on entry and exit rates and in the identification of the so-called “histidine gate” at position 64 through which ≈90% of flux between solvent and the distal pocket passes. We also show with six-dimensional calculations that the minimum free-energy pathway of escape through the histidine gate is a “knock-on” mechanism in which motion of the ligand and the gate are sequential and interdependent. In total, these results suggest that such TPT simulations are indeed a promising approach to overcome the practical time-scale limitations of MD to allow reliable estimation of transition mechanisms and rates among metastable states.
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DOI：
10.1073/pnas.0914540107
发表时间：
2010-03-16
影响因子：
11.1
作者：
Abrams, Cameron F.;Vanden-Eijnden, Eric
通讯作者：
Vanden-Eijnden, Eric
影响因子：
3.4
作者：
Anselmi, Massimiliano;Di Nola, Alfredo;Amadei, Andrea
通讯作者：
Amadei, Andrea
影响因子：
3.4
作者：
Bossa, C;Anselmi, M;Di Nola, A
通讯作者：
Di Nola, A
影响因子：
5.5
作者：
Lapelosa, Mauro;Abrams, Cameron F.
通讯作者：
Abrams, Cameron F.
影响因子：
4.4
作者：
Maragliano, Luca;Fischer, Alexander;Ciccotti, Giovanni
通讯作者：
Ciccotti, Giovanni