Assessment of Halogen Off-Center Point-Charge Models Using Explicit Solvent Simulations

20 September 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Compounds containing halogens can form halogen bonds (XBs) with biological targets such as proteins and membranes due to their anisotropic electrostatic potential. To accurately describe this anisotropy, off-center point-charge (EP) models are commonly used in force field methods allowing the description of XBs at the molecular mechanics and molecular dynamics level. Various EP implementations have been documented in the literature and despite being efficient in reproducing protein-ligand geometries and sampling of XBs, it is unclear how well these EP models predict experimental properties such as hydration free energies (\dGhyd{}), which are often used to validate force field performance. In this work, we report the first assessment of three EP models using alchemical free energy calculations to predict \dGhyd{} values. We show that describing the halogen anisotropy using some EP models can lead to a slight improvement in the prediction of the \dGhyd{} when compared with the models without EP, especially for the chlorinated compounds, however, this improvement is not related to the establishment of XBs but is most likely due to the improvement of the sampling of hydrogen bonds (HBs). We also highlight the importance of the choice of the EP model, especially for the iodinated molecules since a slight tendency to improve the prediction is observed for compounds with a larger $\sigma$--hole but significantly worse results were obtained for compounds that are weaker XB donors.


halogen bonds
hydration free energy
force field
RESP charges

Supplementary materials

Supporting Information
Supporting Tables and Figures (PDF)


Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.