Department of Pharmacy, Università "G. D'Annunzio" Di Chieti-Pescara, Chieti, Italy.
J Comput Aided Mol Des. 2023 Dec;37(12):707-719. doi: 10.1007/s10822-023-00532-2. Epub 2023 Sep 25.
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) of two Au(I)-biscarbene derivatives, [Au(9-methylcaffein-8-ylidene)] and [Au(1,3-dimethylbenzimidazole-2-ylidene)], able to interact with DNA G-quadruplex motif. We found that ΔE and ligand-receptor pair interaction energies (E) 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 and E, 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 values describe the binding efficiency of metal-based binders to DNA Gq more accurately than ΔE. 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描述了配体-受体相互作用，就像 Au(I)-双卡宾/DNA G-四链体复合物一样。在之前的工作中（J Comput Aided Mol Des2022，36，851-866），我们使用从头算 FMO2 方法，在 RI-MP2/6-31G*理论水平上，采用 PCM [1]溶剂化方法，计算了两个能够与 DNA G-四链体基序相互作用的 Au(I)-双卡宾衍生物的结合能（ΔE）：[Au(9-甲基caffein-8-亚基)]和[Au(1,3-二甲基苯并咪唑-2-亚基)]。我们发现，ΔE 和配体-受体对相互作用能（E）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，并将此问题归因于对包含金属原子的片段之间嵌入的电荷转移能的高估。在这项工作中，为了提高 FMO 方法预测与 DNA G-四链体（Gq）相互作用的金属基配体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，考虑 Hartree-Fock（HF）和后 Hartree-Fock 方法，即 RI-MP2；（ii）两种（FMO2）和三种（FMO3）方法；（iii）基组大小（极化函数和双 ζ 与三 ζ）和（iv）嵌入静电势（ESP）。此外，系统地采用了部分屏蔽方法来模拟每个计算的溶剂屏蔽效果。我们发现，使用对所有原子进行屏蔽点电荷计算得到的静电势（ESP-SPTC）对ΔE 和 E 的准确性有重大影响，消除了对电荷转移能的高估，并导致能量值具有与典型实验结合能相当的大小。通过这种计算方法，E 值比ΔE 更准确地描述了金属基配体与 DNA Gq 的结合效率。因此，为了用 FMO 方法研究含金属系统的结合过程，应该考虑采用部分屏蔽溶剂方法和 ESP-SPCT。建议在含有金属的生物系统的 FMO 计算中采用这种计算方案，尤其是当采用默认的 ESP 处理方法会导致可疑结果时。
