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
σ 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 σ hole is modeled by a massless
point charge attached to the halogen atom and referred to as an explicit
σ 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 Å from the bromine atomic center is suggested as a universal
model for the ESH.