Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 24, Issue 20, Pages 4812-4825Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2016.06.034
Keywords
Sigma hole; Halogen bond; CHARMM; Halogen; Drug design; CGenFF
Funding
- National Institutes of Health [GM070855, GM072558, GM037554, F32GM109632]
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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. (C) 2016 Elsevier Ltd. All rights reserved.
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