Speaker
Description
Abstract:
The correct reproduction of the molecular electrostatic potential (MEP) is very important for the analysis and account of electrostatic interactions in molecular modeling. The classical force fields for biomolecules and drug-like molecules usually use the atomic point charges to model and describe MEP. The equilibration of atomic (orbital) electronegativities for the computation of partial atomic charges is one of the approaches and it was demonstrated how the formalism of the theory of electrical circuits can be applied for that. However, it has been pointed out in literature that such an approximation is not always enough, and some groups, like amino group or heavy halogens, require the use of anisotropic model for better description of their MEP. At the same time, the formally charged groups have not been as extensively and systematically studied as their neutral counterparts. We have demonstrated that the anisotropic models for formally charged groups do bring improvements in the reference MEP reproduction, that are comparable in magnitude to those for neutral groups. Comparison of the obtained charges with those produced by means of various computational schemes has shown that the developed charge models are well suited for application in many areas of molecular modeling and QSAR/QSPR studies.
The relative importance of various electronic effects in change calculation schemes was also estimated. First, the account of formal charges is of primordial importance. Second, the nearest neighbors account is the next in significance. Third, the explicit account of inductive effect in empirical charge calculation schemes was shown to significantly improve the quality of MEP reproduction. Fourth, the contribution of polarization is indirectly assessed. Surprisingly, it is of the order of magnitude of the inductive effect even for the molecular systems, for which it is anticipated to be more significant. Finally, the relative importance of anisotropic effects in neutral molecules was additionally analyzed.
A new quadrupole-based approach for halogen bonding description was also tested. It was shown that the suggested electrostatics model built by the addition of fixed atomic quadrupoles to heavy halogen atoms, provides a consistently good description of intermolecular interactions between halogen atom and both hydrogen bond donors and halogen bond acceptors. The solvation free energy differences for F-, Cl-, Br-, and I-substituted benzenes are in excellent agreement with the experimental values. The quadrupoles used were obtained by fitting electrostatic models to an ab initio reference MEP and are independent of the force field. This approach of quadrupole addition should work for any kind of numerical experiment in the field of medicinal chemistry ranging from a direct molecular dynamics investigation of a protein−ligand system to an incorporation into scoring functions and QSAR/QSPR models.
