Computation of Standard Binding Free Energies of Polar and Charged Ligands to the Glutamate Receptor GluA2
Computation of Standard Binding Free Energies of Polar and Charged Ligands to the Glutamate Receptor GluA2
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DOI：
10.1021/jp412195m
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发表时间：
2014-02-20
影响因子：
3.3
通讯作者：
Kuyucak, Serdar
中科院分区：
文献类型：
--
作者：
Heinzelmann, Germano;Chen, Po-Chia;Kuyucak, Serdar
精确计算小分子与蛋白质的结合亲和力有可能成为合理药物设计的重要工具。在这项研究中，我们使用的自由能微扰（FEP）的方法与限制计算的标准结合自由能的五个配体（ACPA，AMPA，CNQX，DNQX，谷氨酸）谷氨酸受体GluA 2，这在突触传递中起着至关重要的作用。为了解决带电荷配体的FEP计算中的收敛问题，我们使用了一种方案，其中配体在结合位点耦合，同时在本体溶液中解耦。从构象，旋转，和平移熵的标准结合自由能的贡献是通过施加/释放相应的限制体/结合位点的配体。我们还采用了限制和释放的方法，这有助于解决FEP计算中的收敛问题。我们的结果是在良好的协议与实验值为所有五个配体，包括带电的FEP计算中经常出现问题。我们还分析了不同的贡献，每个配体GluA 2的结合自由能，并讨论这些相互作用的性质。
Accurate calculation of the binding affinity of small molecules to proteins has the potential to become an important tool in rational drug design. In this study, we use the free energy perturbation (FEP) method with restraints to calculate the standard binding free energy of five ligands (ACPA, AMPA, CNQX, DNQX, and glutamate) to the glutamate receptor GluA2, which plays an essential role in synaptic transmission. To deal with the convergence problem in FEP calculations with charged ligands, we use a protocol where the ligand is coupled in the binding site while it is decoupled in bulk solution simultaneously. The contributions from the conformational, rotational, and translational entropies to the standard binding free energy are determined by applying/releasing respective restraints to the ligand in bulk/binding site. We also employ the confine-and-release approach, which helps to resolve convergence problems in FEP calculations. Our results are in good agreement with the experimental values for all five ligands, including the charged ones which are often problematic in FEP calculations. We also analyze the different contributions to the binding free energy of each ligand to GluA2 and discuss the nature of these interactions.