title: Impact of Quadrupolar Electrostatics on Atoms Adjacent to the Sigma-Hole in Condensed-Phase Simulations.
abstract: Halogenation is one of the cases for which advanced molecular simulation methods are mandatory for quantitative and predictive studies. The present work provides a systematic investigation of the importance of higher-order multipoles on specific sites of halobenzenes, other than the halogen, for static and dynamic properties in condensed-phase simulations. For that purpose, solute-solvent interactions using point charge (PC), multipole (MTP), and hybrid point charge/multipole (HYB) electrostatic models are analyzed in regions of halogen bonding and extended to regions of π orbitals of phenyl carbons. Using molecular dynamics simulations and quantum chemical methods, it is found that the sigma-hole does not only affect the halogen and the carbon bound to it but its effect extends to the carbons adjacent to the CX bond. This effect increases with the magnitude of the positive potential of the sigma-hole. With the MTP and HYB3 models, all hydration free energies of the PhX compounds are reproduced within 0.1 kcal/mol. Analysis of pair distribution functions and hydration free energies of halogenated benzenes provides a microscopic explanation why "point charge"-based representations with off-site charges fail in reproducing thermodynamic properties of the sigma-hole. Application of the hybrid models to study protein-ligand binding demonstrates both their accuracy and computational efficiency.
authors.affiliation: Department of Chemistry, University of Basel , Klingelbergstrasse 80, 4056 Basel, Switzerland.
authors.forename: Krystel
authors.initials: K
authors.lastname: El Hage
authors.affiliation: Max Planck Institute for Polymer Research , Ackermannweg 10, 55128 Mainz, Germany.
authors.forename: Tristan
authors.initials: T
authors.lastname: Bereau
authors.affiliation: Department of Chemistry, University of Basel , Klingelbergstrasse 80, 4056 Basel, Switzerland.|Department of Chemistry, Aarhus University , Langelandsgade 140, 8000 Aarhus C, Denmark.
authors.forename: Sofie
authors.initials: S
authors.lastname: Jakobsen
authors.affiliation: Department of Chemistry, University of Basel , Klingelbergstrasse 80, 4056 Basel, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Meuwly