Thermodynamic integration to predict host-guest binding affinities.
Thermodynamic integration to predict host-guest binding affinities.
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DOI：
10.1007/s10822-012-9542-5
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发表时间：
2012-05
影响因子：
3.5
通讯作者：
McCammon, J. Andrew
中科院分区：
文献类型：
--
作者：
Lawrenz, Morgan;Wereszczynski, Jeff;Ortiz-Sanchez, Juan Manuel;Nichols, Sara E.;McCammon, J. Andrew
采用炼金术自由能方法和显式溶剂分子动力学模拟，作为盲目预测竞赛SAMPL3的一部分，计算了七个客体与一个非环葫芦-[n]脲主体的结合自由能。这些预测包括确定主和客体的质子化状态，对接姿势的产生，以及使用热力学积分计算束缚自由能。由参考实验结果得到的均方根误差为3.6kcal摩尔−1，R2相关系数为0.51.当采用周期诱导自由能修正时，最大贡献者Guest 6与实验的一致性提高了1.7kcal摩尔−1。对其他配体的修正明显较小，RMSE总共降低了0.4kcal−1。我们将模拟过程中主-客体体系的性质与计算自由能的误差联系起来。总体而言，我们表明，在这里研究的带电主客系统，在未经确认的对接姿势下初始化，对准确的炼金术模拟方法提出了挑战。
An alchemical free energy method with explicit solvent molecular dynamics simulations was applied as part of the blind prediction contest SAMPL3 to calculate binding free energies for seven guests to an acyclic cucurbit-[n]uril host. The predictions included determination of protonation states for both host and guests, docking pose generation, and binding free energy calculations using thermodynamic integration. We found a root mean square error (RMSE) of 3.6 kcal mol−1 from the reference experimental results, with an R2 correlation of 0.51. The agreement with experiment for the largest contributor to this error, guest 6, is improved by 1.7 kcal mol−1 when a periodicity-induced free energy correction is applied. The corrections for the other ligands were significantly smaller, and altogether the RMSE was reduced by 0.4 kcal mol−1. We link properties of the host-guest systems during simulation to errors in the computed free energies. Overall, we show that charged host-guest systems studied here, initialized in unconfirmed docking poses, present a challenge to accurate alchemical simulation methods.
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