Parametrization of halogen bonds in the CHARMM general force field: Improved treatment of ligand–protein interactions

Abstract

A halogen bond is a highly directional, non-covalent interaction between a halogen atom and another electronegative atom. It arises due to the formation of a small region of positive electrostatic potential opposite the covalent bond to the halogen, called the “sigma hole.” Empirical force fields in which the electrostatic interactions are represented by atom-centered point charges cannot capture this effect because halogen atoms usually carry a negative charge and therefore interact unfavorably with other electronegative atoms. A strategy to overcome this problem is to attach a positively charged virtual particle to the halogen. In this work, we extend the additive CHARMM General Force Field (CGenFF) to include such interactions in model systems of phenyl-X, with X being Cl, Br or I including di- and trihalogenated species. The charges, Lennard-Jones parameters, and halogen-virtual particle distances were optimized to reproduce the orientation dependence of quantum mechanical interaction energies with water, acetone, and N-methylacetamide as well as experimental pure liquid properties and relative hydration free energies with respect to benzene. The resulting parameters were validated in molecular dynamics simulations on small-molecule crystals and on solvated protein-ligand complexes containing halogenated compounds. The inclusion of positive virtual sites leads to better agreement across experimental observables, including preservation of ligand binding poses as a direct result of the improved representation of halogen bonding.

The Interaction Modes of Haloimidazolium Salts in Solution

“…For instance, it is difficult to describe the σ‐hole on the halogen atoms by a fixed point charge model. A recent study on the parameterization of halobenzenes with the CHARMM force field uses a massless charged particle placed collinear to the C−X sigma bond to mimic the positive charged σ‐hole . We adopted this approach to model the haloimidazolium salts.…”

Absolute binding free energies for octa-acids and guests in SAMPL5

“…We reparametrized G4 (Fig. 6c) and added a lonepair to the bromine group, similarly to this work [33] (see Supporting Information for the parameter files). The resulting OAH-G4 and OAMe-G4 complexes were solvated and we added 25 mM of NaCl, which reproduces the ionic strength of 10 mM Na 3 PO 4 at pH 11.…”

“…The σ -hole parameters for G4 were generated similarly to work in Ref. [33]. All parameters are included in the Supporting Information.…”

Large scale relative protein ligand binding affinities using non-equilibrium alchemy

“…Ligands containing chlorine and bromine were decorated with virtual particles carrying a small positive charge, following the rules for GAFF 74 and CGenFF. 75 Having parameterized the ligands, hybrid structures and topologies for the ligand pairs were generated using pmx. A mapping between the atoms of two molecules was established following a predened set of rules to ensure minimal perturbation and system stability during the simulations.…”