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

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TitleParametrization of halogen bonds in the CHARMM general force field: Improved treatment of ligand-protein interactions.
Publication TypeJournal Article
Year of Publication2016
AuthorsGutiérrez, ISoteras, Lin, F-Y, Vanommeslaeghe, K, Lemkul, JA, Armacost, KA, Brooks, CL, Mackerell, AD
JournalBioorg Med Chem
Date Published2016 Oct 15
KeywordsHalogens, Ligands, Proteins, Quantum Theory, Static Electricity, Thermodynamics

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.

Alternate JournalBioorg. Med. Chem.
PubMed ID27353885
PubMed Central IDPMC5053860
Grant ListF32 GM109632 / GM / NIGMS NIH HHS / United States
R01 GM037554 / GM / NIGMS NIH HHS / United States
R01 GM070855 / GM / NIGMS NIH HHS / United States
R01 GM072558 / GM / NIGMS NIH HHS / United States