title: 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.
authors.affiliation: Life Sciences Department, Barcelona Supercomputing Center, Jordi Girona 29, Barcelona 08034, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Soteras Gutiérrez
authors.affiliation: Computer-Aided Drug Design Center, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, United States.
authors.forename: Fang-Yu
authors.initials: FY
authors.lastname: Lin
authors.affiliation: 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.
authors.forename: Kenno
authors.initials: K
authors.lastname: Vanommeslaeghe
authors.affiliation: Computer-Aided Drug Design Center, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, United States.
authors.forename: Justin A
authors.initials: JA
authors.lastname: Lemkul
authors.affiliation: Department of Chemistry and Biophysics, University of Michigan, 930 North University Avenue, Ann Arbor, MI 48109, United States.
authors.forename: Kira A
authors.initials: KA
authors.lastname: Armacost
authors.affiliation: Department of Chemistry and Biophysics, University of Michigan, 930 North University Avenue, Ann Arbor, MI 48109, United States.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Brooks
authors.affiliation: 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.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: MacKerell
mesh_terms: D006219:Halogens / Q000737:chemistry*; D008024:Ligands; D011506:Proteins / Q000737:chemistry*; D011789:Quantum Theory; D055672:Static Electricity; D013816:Thermodynamics
chemical_list: D006219:Halogens; D008024:Ligands; D011506:Proteins
keywords: CGenFF; CHARMM; Drug design; Halogen; Halogen bond; Sigma hole