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首页> 外文期刊>The journal of physical chemistry, A. Molecules, spectroscopy, kinetics, environment, & general theory >Protein-ligand interaction energies with dispersion corrected density functional theory and high-level wave function based methods
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Protein-ligand interaction energies with dispersion corrected density functional theory and high-level wave function based methods

机译：蛋白质-配体相互作用能，采用色散校正密度泛函理论和基于高阶波函数的方法

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With dispersion-corrected density functional theory (DFT-D3) intermolecular interaction energies for a diverse set of noncovalently bound protein-ligand complexes from the Protein Data Bank are calculated. The focus is on major contacts occurring between the drug molecule and the binding site. Generalized gradient approximation (GGA), meta-GGA, and hybrid functionals are used. DFT-D3 interaction energies are benchmarked against the best available wave function based results that are provided by the estimated complete basis set (CBS) limit of the local pair natural orbital coupled-electron pair approximation (LPNO-CEPA/1) and compared to MP2 and semiempirical data. The size of the complexes and their interaction energies (ΔE_(PL)) varies between 50 and 300 atoms and from -1 to -65 kcal/mol, respectively. Basis set effects are considered by applying extended sets of triple- to quadruple-Χ quality. Computed total ΔE_(PL) values show a good correlation with the dispersion contribution despite the fact that the protein-ligand complexes contain many hydrogen bonds. It is concluded that an adequate, for example, asymptotically correct, treatment of dispersion interactions is necessary for the realistic modeling of protein-ligand binding. Inclusion of the dispersion correction drastically reduces the dependence of the computed interaction energies on the density functional compared to uncorrected DFT results. DFT-D3 methods provide results that are consistent with LPNO-CEPA/1 and MP2, the differences of about 1-2 kcal/mol on average (<5% of ΔE_(PL)) being on the order of their accuracy, while dispersion-corrected semiempirical AM1 and PM3 approaches show a deviating behavior. The DFT-D3 results are found to depend insignificantly on the choice of the short-range damping model. We propose to use DFT-D3 as an essential ingredient in a QM/MM approach for advanced virtual screening approaches of protein-ligand interactions to be combined with similarly "first-principle" accounts for the estimation of solvation and entropic effects.
机译：使用分散校正的密度泛函理论（DFT-D3），可以计算蛋白质数据库中各种非共价结合的蛋白质-配体复合物的分子间相互作用能。重点是在药物分子和结合位点之间发生的主要接触。使用了广义梯度近似（GGA），meta-GGA和混合函数。将DFT-D3相互作用能与基于最佳可用波函数的结果进行基准比较，该结果由本地对自然轨道耦合电子对近似值（LPNO-CEPA / 1）的估计完整基集（CBS）限制提供，并与MP2比较和半经验数据。配合物的大小及其相互作用能（ΔE_（PL））分别在50到300个原子之间和-1至-65 kcal / mol之间变化。通过应用三重到四重X质量的扩展集，可以考虑基础集效应。尽管蛋白质-配体络合物包含许多氢键，但计算出的总ΔE_（PL）值与分散作用具有良好的相关性。结论是，对于蛋白质-配体结合的真实模型，对分散体相互作用进行充分的例如渐近正确的处理是必要的。与未校正的DFT结果相比，包含色散校正可以大大减少所计算的相互作用能对密度泛函的依赖性。 DFT-D3方法提供的结果与LPNO-CEPA / 1和MP2一致，平均差异约为1-2 kcal / mol（<ΔE_（PL）的5％），其准确性在数量级上，而分散校正的半经验AM1和PM3方法显示出偏差的行为。发现DFT-D3的结果与短程阻尼模型的选择无关紧要。我们建议使用DFT-D3作为QM / MM方法的基本成分，用于蛋白质-配体相互作用的高级虚拟筛选方法，与类似的“第一原理”结合使用，以评估溶剂化和熵作用。

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