Accurate Receptor-Ligand Binding Free Energies from Fast QM Conformational Chemical Space Sampling.
Accurate Receptor-Ligand Binding Free Energies from Fast QM Conformational Chemical Space Sampling.
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DOI：
10.3390/ijms22063078
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发表时间：
2021-03-17
影响因子：
5.6
通讯作者：
Stein M
中科院分区：
文献类型：
--
作者：
Boz E;Stein M
小分子受体结合由弱的非共价相互作用如范德华氢键或静电作用主导。计算这些非共价配体-受体相互作用在准确性和有效性方面对计算手段是一个挑战，因为配体可以以许多热可及构象结合。构象旋转异构体整体采样工具（CREST）使用迭代方案来有效地对构象空间进行采样，并使用半经验的“几何、频率、非共价、扩展紧密结合”（GFN 2-xTB）方法来计算能量。这种组合的方法被应用于盲预测的模式和自由能的一组10个药物分子配体的结合葫芦[n]脲CB[8]受体从最近的“蛋白质和配体建模的统计评估”（SAMPL）的挑战，包括吗啡，氢吗啡，可卡因，芬太尼，氯胺酮。对于每个系统，构象空间被充分采样的自由配体和配体-受体复合物使用量子化学哈密顿量。众多的结构构成了最终的适形-旋转异构体系综，然后计算结合的自由能。对于那些大的和复杂的分子，结果与实验值符合良好，平均误差为3千卡/摩尔。GFN 2-xTB的结合能进行了验证先进的密度泛函理论计算，发现是在良好的协议。自动化QM采样工作流程的有效性允许扩展到其他复杂的分子相互作用场景。
Small molecule receptor-binding is dominated by weak, non-covalent interactions such as van-der-Waals hydrogen bonding or electrostatics. Calculating these non-covalent ligand-receptor interactions is a challenge to computational means in terms of accuracy and efficacy since the ligand may bind in a number of thermally accessible conformations. The conformational rotamer ensemble sampling tool (CREST) uses an iterative scheme to efficiently sample the conformational space and calculates energies using the semi-empirical ‘Geometry, Frequency, Noncovalent, eXtended Tight Binding’ (GFN2-xTB) method. This combined approach is applied to blind predictions of the modes and free energies of binding for a set of 10 drug molecule ligands to the cucurbit[n]urils CB[8] receptor from the recent ‘Statistical Assessment of the Modeling of Proteins and Ligands’ (SAMPL) challenge including morphine, hydromorphine, cocaine, fentanyl, and ketamine. For each system, the conformational space was sufficiently sampled for the free ligand and the ligand-receptor complexes using the quantum chemical Hamiltonian. A multitude of structures makes up the final conformer-rotamer ensemble, for which then free energies of binding are calculated. For those large and complex molecules, the results are in good agreement with experimental values with a mean error of 3 kcal/mol. The GFN2-xTB energies of binding are validated by advanced density functional theory calculations and found to be in good agreement. The efficacy of the automated QM sampling workflow allows the extension towards other complex molecular interaction scenarios.
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