Improving the accuracy of the FMO binding affinity prediction of ligand-receptor complexes containing metals

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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10822-023-00532-2.