On Extension of the Current Biomolecular Empirical Force Field for the Description of Halogen Bonds

Until recently, the description of halogen bonding by standard molecular mechanics has been poor, owing to the lack of the so-called sigma hole localized at the halogen. This region of positive electrostatic potential located on top of a halogen atom explains the counterintuitive attraction of halogenated compounds interacting with Lewis bases. In molecular mechanics, the sigma hole is modeled by a massless point charge attached to the halogen atom and referred to as an explicit sigma hole (ESH). Here, we introduce and compare three methods of ESH construction, which differ in the complexity of the input needed. The molecular mechanical dissociation curves of three model complexes containing bromine are compared with accurate CCSD(T)/CBS data. Furthermore, the performance of the Amber force field enhanced by the ESH on geometry characteristics is tested on the casein kinase 2 protein complex with seven brominated inhibitors. It is shown how various schemes depend on the selection of the ESH parameters and to what extent the energies and geometries are reliable. The charge of 0.2e placed 1.5 angstrom from the bromine atomic center is suggested as a universal model for the ESH.