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

Area of Science:

• Computational chemistry
• Molecular modeling
• Biophysics

Background:

• Halogen bonds (XBs) are crucial interactions between halogenated compounds and biological targets.
• Off-center point-charge (EP) models are used in molecular mechanics and dynamics to describe halogen anisotropy.
• Experimental validation of EP models using hydration free energies (ΔGhyd) is lacking.

Purpose of the Study:

• To assess the performance of three EP models in predicting hydration free energies (ΔGhyd).
• To evaluate the impact of EP models on the accuracy of force field predictions for halogenated compounds.
• To understand the relationship between EP model implementation and the prediction of halogen bonding and hydration properties.

Main Methods:

• Alchemical free energy calculations were employed to predict ΔGhyd values.
• Three different off-center point-charge (EP) models were tested.
• The predictive accuracy of EP models was compared against models without explicit charge centers.

Main Results:

• EP models showed a slight improvement in ΔGhyd prediction compared to non-EP models, particularly for chlorinated compounds.
• The observed improvement was primarily attributed to enhanced sampling of hydrogen bonds, not direct halogen bond interactions.
• The choice of EP model significantly impacted results, especially for iodinated molecules, with mixed outcomes depending on σ-hole strength.

Conclusions:

• EP models offer a marginal benefit for ΔGhyd prediction, mainly through improved hydrogen bond sampling.
• The effectiveness of EP models is compound-specific and depends on the halogen type and electronic properties (e.g., σ-hole).
• Careful selection of EP models is essential for accurate molecular simulations involving halogenated compounds.