Role of exchange and correlation in the real external prediction of mutagenicity: performance of hybrid and meta-hybrid exchange-correlation functionals

Quantum-mechanical exchange and correlation interactions between electrons are quite crucial in deciding molecular geometry and properties. Such electronic interactions can have a significant role in the reliability of a quantitative structure-activity relationship (QSAR) because the biological activities of the chemicals can be described as a function of the molecular structure through the QSARs which are routinely based on the quantum-mechanical molecular descriptors. In this work, we present a detailed analysis of the effect of the quantum-mechanical exchange and correlation on the internal stability and external predictivity of a QSAR model based on the quantum-mechanical molecular descriptors while modeling the mutagenic activity of a set of 51 nitrated-polycyclic aromatic hydrocarbons (PAHs). For this, various molecular descriptors are computed using electronic structure methods such as the Hartree-Fock (HF) method, and density functional theory (DFT) employing only the exchange functionals (HFX, B88), pure exchange and correlation functionals (HFX + LYP, BLYP), hybrid (B3LYP), meta (M06-L), and meta-hybrid (M06, M06-2X) exchange-correlation (XC) functionals. To further analyze the role of electron-correlation, QSAR models are also developed using the descriptors incorporating mainly the effect of electron-correlation. The external predictivity of the developed models is assessed through state-of-the-art external validation parameters employing an external prediction set of compounds. A comparison of the quality of the models developed with the descriptors computed using different electronic structure methods revealed that the exchange interactions are quite critical along with the electron-correlation in modeling the mutagenicity. Notably, for most of the models, electron-correlation based descriptors are found to be highly reliable when computed using the hybrid XC functionals, particularly B3LYP and M06-2X.