Free-energy perturbation and quantum mechanical study of SAMPL4 octa-acid host–guest binding energies
Free-energy perturbation and quantum mechanical study of SAMPL4 octa-acid host–guest binding energies
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DOI：
10.1007/s10822-014-9739-x
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发表时间：
2014-04
影响因子：
3.5
通讯作者：
P. Mikulskis;D. Cioloboc;Milica Andrejic;Sakshi Khare;Joakim Brorsson;S. Genheden;R. Mata;Pär Söderhjelm;U. Ryde
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文献类型：
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作者：
P. Mikulskis;D. Cioloboc;Milica Andrejic;Sakshi Khare;Joakim Brorsson;S. Genheden;R. Mata;Pär Söderhjelm;U. Ryde
在SAMPL4盲测挑战中，我们用四种不同的方法估计了九个环羧酸客体分子与八酸宿主结合的自由能。首先，我们使用标准自由能微扰计算相对结合亲和力，在分子力学(MM)水平上用TIP3P水、Gaff力场和两组不同的主客体电荷，用约束静电势或AM1-BCC方法得到。两个电荷组都给出了很好且几乎相同的结果，与实验结果相比，平均绝对偏差(MAD)为4kJ/mol，相关系数(R2)为0.8。其次，我们试图用28,800个选定快照的密度泛函理论(DFT)计算和非Boltzmann Bennett接受比方法来改进这些预测，但这导致了更糟糕的结果，可能是因为MM和DFT势能函数之间的差异太大。第三，我们尝试使用最小化的DFT结构来计算绝对亲和度。这给出了中等质量的结果，MADS为5-9kJ/mol，R2=100.6-0.8，这取决于结构的获得方式。最后，我们尝试用单激发和双激发的局域耦合团簇计算和三激发的非迭代微扰处理(LCCSD(T0))，采用可极化的多极相互作用与超分子对的方法来改进这些结果。不幸的是，这只是降低了预测，可能是因为在DFT和LCCSD(T0)水平上获得的溶剂化能之间不匹配。
We have estimated free energies for the binding of nine cyclic carboxylate guest molecules to the octa-acid host in the SAMPL4 blind-test challenge with four different approaches. First, we used standard free-energy perturbation calculations of relative binding affinities, performed at the molecular-mechanics (MM) level with TIP3P waters, the GAFF force field, and two different sets of charges for the host and the guest, obtained either with the restrained electrostatic potential or AM1-BCC methods. Both charge sets give good and nearly identical results, with a mean absolute deviation (MAD) of 4 kJ/mol and a correlation coefficient (R2) of 0.8 compared to experimental results. Second, we tried to improve these predictions with 28,800 density-functional theory (DFT) calculations for selected snapshots and the non-Boltzmann Bennett acceptance-ratio method, but this led to much worse results, probably because of a too large difference between the MM and DFT potential-energy functions. Third, we tried to calculate absolute affinities using minimised DFT structures. This gave intermediate-quality results with MADs of 5–9 kJ/mol andR2= 0.6–0.8, depending on how the structures were obtained. Finally, we tried to improve these results using local coupled-cluster calculations with single and double excitations, and non-iterative perturbative treatment of triple excitations (LCCSD(T0)), employing the polarisable multipole interactions with supermolecular pairs approach. Unfortunately, this only degraded the predictions, probably because of a mismatch between the solvation energies obtained at the DFT and LCCSD(T0) levels.