Parameterization of a drug molecule with a halogen σ-hole particle using ffTK: Implementation, testing, and...

Area of Science:

• Computational chemistry
• Molecular modeling
• Drug discovery

Background:

• Halogen atoms in drugs enhance binding affinity via halogen bonding.
• Halogen bonding involves a "σ-hole" on the halogen atom.
• Mimicking the σ-hole in force fields is crucial for accurate simulations.

Purpose of the Study:

• To integrate lone pair (LP) particle support into the ffTK toolkit.
• To improve the parameterization of halogenated molecules in molecular simulations.
• To enhance the accuracy of electrostatic interactions involving halogen atoms.

Main Methods:

• Incorporated LP particle functionality into the ffTK automated force field parameterization toolkit.
• Utilized VMD plugin for molecular visualization and parameterization.
• Applied the updated ffTK to parameterize the halogenated drug molecule AT130.

Main Results:

• The ffTK toolkit now supports LP particles for halogen atoms.
• Parameterization with LP particles significantly improved the electrostatic response accuracy of AT130.
• Optimization of parameters with LP particles greatly enhanced protein-ligand binding performance.

Conclusions:

• The updated ffTK with LP particle support accurately models halogen bonding effects.
• This advancement improves molecular simulations for drug design and discovery.
• Enhanced electrostatic modeling leads to better prediction of drug-target interactions.