Scalable Anisotropic Shape and Electrostatic Models for Biological Bromine Halogen Bonds

Area of Science:

• Computational chemistry
• Biomolecular modeling
• Drug discovery

Background:

• Halogens are crucial in drug and metabolite structures.
• Current molecular modeling methods inadequately represent halogen interactions, particularly halogen bonds.
• Accurate modeling of halogen bonds is essential for understanding protein-ligand specificity.

Purpose of the Study:

• To develop accurate and efficient methods for modeling the energies and geometries of halogen interactions in biomolecular complexes.
• To create a force field that captures the anisotropic properties of halogens.

Main Methods:

• Developed a set of potential energy functions based on fundamental physical properties of halogens.
• Incorporated an angular dependence into the Lennard-Jones potential to model the steric repulsion and anisotropic shape of bromine.
• Applied this to model the charge distribution and electrostatic potential, treating shape and charge anisotropically.
• Validated against crystallographic, calorimetric, and ab initio data for bromine halogen bonds.

Main Results:

• The new energy functions accurately model anisotropic structure-energy relationships for halogen interactions.
• Electrostatics alone are insufficient; a modified van der Waals radius (flattened) is required for short-range halogen bonds.
• The force field (ffBXB) accurately models bromine interactions with oxygen acceptors.
• The model is tunable based on substituent effects (Hammett constants).

Conclusions:

• The ffBXB force field provides an accurate and anisotropic treatment of halogen bonds in biological contexts.
• This method improves the modeling of halogen interactions, crucial for drug design.
• Enables more precise prediction of protein-ligand interactions involving halogens.