Predicting ligand binding affinity with alchemical free energy methods in a polar model binding site.
Predicting ligand binding affinity with alchemical free energy methods in a polar model binding site.
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使用炼金术自由能方法预测极性模型结合位点中的配体结合亲和力。
DOI：
10.1016/j.jmb.2009.09.049
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发表时间：
2009-12-11
影响因子：
5.6
通讯作者：
Shoichet, Brian K.
中科院分区：
文献类型：
--
作者：
Boyce, Sarah E.;Mobley, David L.;Rocklin, Gabriel J.;Graves, Alan P.;Dill, Ken A.;Shoichet, Brian K.
我们提出了一个有机配体分子结合到T4溶菌酶（L99 A/M102 Q）的一个轻微的极性工程空腔网站的实验和建模研究相结合。为了建模，我们计算了炼金术的绝对结合自由能。这些是对13种不同的、先前未测试的候选配体分子进行的前瞻性盲法测试。我们预测有8种化合物会与空腔结合，5种不会;在这个水平上，13个预测中有11个是正确的。可测量的绝对结合能的RMS误差为1.8 kcal/mol。此外，我们计算了相对结合自由能为6苯酚衍生物从两个已知的配体：苯酚和邻苯二酚。相对自由能预测的平均RMS误差为2.5（苯酚）和1.1（邻苯二酚）kcal/mol。为了理解这些结果在原子分辨率，我们获得了X-射线共配合物的结构的9个不同的配体和所有6个苯酚类似物。预测的姿势对实验的平均RMSD为2.0 μ m（多样集）、1.8 μ m（苯酚衍生的预测）和1.2 μ m（邻苯二酚衍生的预测）。我们发现，要预测准确的亲和力和秩序需要在结合位点的配体的近天然的起始取向。未预料到的结合模式，多配体结合，和蛋白质构象变化都证明了具有挑战性的自由能方法。我们相信，这些结果可以帮助指导未来的改进，在物理为基础的绝对结合自由能方法。
We present a combined experimental and modeling study of organic ligand molecules binding to a slightly polar engineered cavity site in T4 lysozyme (L99A/M102Q). For modeling, we computed alchemical absolute binding free energies. These were blind tests performed prospectively on 13 diverse, previously untested candidate ligand molecules. We predicted that eight compounds would bind to the cavity and five would not; 11 of 13 predictions were correct at this level. The RMS error to the measurable absolute binding energies was 1.8 kcal/mol. In addition, we computed relative binding free energies for six phenol derivatives starting from two known ligands: phenol and catechol. The average RMS error in the relative free energy prediction was 2.5 (phenol) and 1.1 (catechol) kcal/mol. To understand these results at atomic resolution, we obtained x-ray co-complex structures for nine of the diverse ligands and for all six phenol analogs. The average RMSD of the predicted pose to the experiment was 2.0Å (diverse set), 1.8Å (phenol derived predictions) and 1.2Å (catechol derived predictions). We found that to predict accurate affinities and rank-orderings required near-native starting orientations of the ligand in the binding site. Unanticipated binding modes, multiple ligand binding, and protein conformational change all proved challenging for the free energy methods. We believe these results can help guide future improvements in physics-based absolute binding free energy methods.
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影响因子：
4.1
作者：
BENNETT, CH
通讯作者：
BENNETT, CH
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
56.9
作者：
BASH, PA;SINGH, UC;KOLLMAN, PA
通讯作者：
KOLLMAN, PA
影响因子：
7.3
作者：
Graves, AP;Brenk, R;Shoichet, BK
通讯作者：
Shoichet, BK
影响因子：
15
作者：
Chang, CE;Gilson, MK
通讯作者：
Gilson, MK