Polarization and charge transfer strongly characterize the ligand-receptor interaction when metal atoms are present, as for the Au(I)-biscarbene/DNA G-quadruplex complexes. In a previous work (J Comput Aided Mol Des2022, 36, 851–866) we used the ab initio FMO2 method at the RI-MP2/6-31G* level of theory with the PCM [1] solvation approach to calculate the binding energy (ΔE^FMO) of two Au(I)-biscarbene derivatives, [Au(9-methylcaffein-8-ylidene)₂]⁺ and [Au(1,3-dimethylbenzimidazole-2-ylidene)₂]⁺, able to interact with DNA G-quadruplex motif. We found that ΔE^FMO and ligand-receptor pair interaction energies (E^INT) show very large negative values making the direct comparison with experimental data difficult and related this issue to the overestimation of the embedded charge transfer energy between fragments containing metal atoms. In this work, to improve the accuracy of the FMO method for predicting the binding affinity of metal-based ligands interacting with DNA G-quadruplex (Gq), we assess the effect of the following computational features: (i) the electron correlation, considering the Hartree–Fock (HF) and a post-HF method, namely RI-MP2; (ii) the two (FMO2) and three-body (FMO3) approaches; (iii) the basis set size (polarization functions and double-ζ vs. triple-ζ) and (iv) the embedding electrostatic potential (ESP). Moreover, the partial screening method was systematically adopted to simulate the solvent screening effect for each calculation. We found that the use of the ESP computed using the screened point charges for all atoms (ESP-SPTC) has a critical impact on the accuracy of both ΔE^FMO and E^INT, eliminating the overestimation of charge transfer energy and leading to energy values with magnitude comparable with typical experimental binding energies. With this computational approach, E^INT values describe the binding efficiency of metal-based binders to DNA Gq more accurately than ΔE^FMO. Therefore, to study the binding process of metal containing systems with the FMO method, the adoption of partial screening solvent method combined with ESP-SPCT should be considered. This computational protocol is suggested for FMO calculations on biological systems containing metals, especially when the adoption of the default ESP treatment leads to questionable results.

当金属原子存在时，极化和电荷转移强烈地表征了配体-受体相互作用，对于 Au(I)-双卡宾/DNA G-四链体复合物而言。在之前的工作 ( J Comput Aided Mol Des 2022, 36, 851–866) 中，我们在 RI-MP2/6-31G* 理论水平上使用从头算 FMO2 方法和 PCM [1] 溶剂化方法来计算结合两种 Au(I)-双卡宾衍生物 [Au(9-methylcaffein-8-ylidene) ₂ ] ⁺和 [Au(1,3-二甲基苯并咪唑-2-ylidene) ₂ ] ⁺的能量 ( ΔE ^FMO ) ，能够相互作用具有 DNA G-四联体基序。我们发现ΔE ^FMO和配体-受体对相互作用能 ( E ^INT ) 显示出非常大的负值，使得与实验数据的直接比较变得困难，并将这个问题与高估含有金属原子的碎片之间的嵌入电荷转移能相关。在这项工作中，为了提高 FMO 方法预测金属配体与 DNA G 四联体 (Gq) 相互作用的结合亲和力的准确性，我们评估了以下计算特征的影响：(i)电子相关性，考虑到Hartree–Fock (HF) 和后 HF 方法，即 RI-MP2；(ii)二体（FMO2）和三体（FMO3）方法；(iii)基组大小（极化函数以及双 z 与三 z ）和(iv)嵌入静电势 (ESP)。此外，系统地采用部分筛选方法来模拟每次计算的溶剂筛选效果。我们发现，使用所有原子的屏蔽点电荷计算的 ESP (ESP-SPTC) 对ΔE ^FMO和E ^INT的精度具有至关重要的影响，消除了对电荷转移能量的高估，并导致能量值大小与典型的实验结合能相当。通过这种计算方法，E ^INT值比ΔEFMO更准确地描述了金属结合剂与 DNA Gq 的结合^效率。因此，用FMO方法研究含金属体系的结合过程，应考虑采用部分筛选溶剂法结合ESP-SPCT。建议将此计算协议用于含有金属的生物系统的 FMO 计算，特别是当采用默认 ESP 处理导致有问题的结果时。