Large variation in electrostatic contours upon addition of steric parameters and the effect of charge calculation schemes in CoMFA on mutagenicity of MX analogues

Abstract

Partial atomic charge is a useful concept to describe physico-chemical properties of a molecule. For this, various schemes have been devised to get reasonable values. Mutagen X is an ideal set to test the effect of partial atomic charge variation. Therefore, we collected data from previous reports and studied various charge schemes. Our systematic study covers 26 charge calculation schemes along with a broad range of levels of theory. Charge calculation schemes include charges from charge equalisation, electrostatic potential fitting, molecular orbital and atomic polar tensor. Calculation levels span from empirical, semi-empirical, Hartree–Fock, density functional and Møller–Plesset 2. We also used two validation statistics for internal prediction. To observe the electrostatic effect accurately during comparative molecular field analysis (CoMFA) modelling, we first studied isolated electrostatic parameters to avoid interaction effect with steric parameters. The results clearly show that adding steric parameters does change statistical conclusions as well as CoMFA maps. Although there was a weak trend that quantum mechanical (QM)-derived charges gave better statistical values, it is not apparent statistically (alpha = 0.05). Particularly, Mülliken population analysis (MPA) did not produce better results. Therefore, when we excluded MPA schemes from QM calculation, the QM-derived charges were found to be significant, i.e. sophisticated charge schemes other than MPA with QM methods were found to be superior to simple empirical charge schemes. In addition, we demonstrated that in order to test charge schemes properly, excluding steric parameter is more important. This work exemplifies Occam's theorem of parsimony. A simpler model is a better model.