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Bioorg Med Chem. 2016 Oct 15;24(20):4812-4825. doi: 10.1016/j.bmc.2016.06.034. Epub 2016 Jun 18.

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

Author information

1
Life Sciences Department, Barcelona Supercomputing Center, Jordi Girona 29, Barcelona 08034, Spain.
2
Computer-Aided Drug Design Center, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, United States.
3
Computer-Aided Drug Design Center, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, United States; Department of Analytical Chemistry and Pharmaceutical Technology (FABI), Center for Pharmaceutical Research (CePhaR), Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, B-1090 Brussels, Belgium.
4
Department of Chemistry and Biophysics, University of Michigan, 930 North University Avenue, Ann Arbor, MI 48109, United States.
5
Computer-Aided Drug Design Center, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, United States. Electronic address: alex@outerbanks.umaryland.edu.

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.

KEYWORDS:

CGenFF; CHARMM; Drug design; Halogen; Halogen bond; Sigma hole

PMID:
27353885
PMCID:
PMC5053860
DOI:
10.1016/j.bmc.2016.06.034
[Indexed for MEDLINE]
Free PMC Article

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