Yu Tang-Qing, Lapelosa Mauro, Vanden-Eijnden Eric, Abrams Cameron F
Courant Institute of Mathematical Sciences, New York University , New York, New York 10012, United States.
J Am Chem Soc. 2015 Mar 4;137(8):3041-50. doi: 10.1021/ja512484q. Epub 2015 Feb 23.
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.
我们在用于肌红蛋白中一氧化碳定位的集体变量空间的细分上使用马尔可夫里程碑分子动力学（MD）模拟，以估计进入、退出和内部位点跳跃的动力学。这种细分是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的，TPT提供了定义最佳里程碑的标准，允许进行短的、独立的、受细胞约束的MD模拟来提供适当加权的动力学数据。我们在两个层面上对所得的动力学模型进行粗粒化：首先，使用晶体学相关的内部腔及其预测的互连和溶剂通道；其次，作为一种三态侧路径方案，其灵感来自于从双分子复合实验发展而来的类似模型。我们在进入和退出速率以及在识别64位所谓的“组氨酸门”方面与实验显示出半定量的一致性，约90%的溶剂与远端口袋之间的通量通过该门。我们还通过六维计算表明，通过组氨酸门逃逸的最小自由能路径是一种“连锁”机制，其中配体和门的运动是相继且相互依赖的。总的来说，这些结果表明，这种TPT模拟确实是一种有前途的方法，可以克服MD实际时间尺度的限制，从而可靠地估计亚稳态之间的转变机制和速率。
