On the force field optimisation of -lactam cores using the force field Toolkit

Area of Science:

• Computational chemistry
• Molecular modeling
• Drug discovery

Background:

• Force field quality is crucial for accurate molecular dynamics (MD) simulations in computer-aided drug design.
• Existing force fields may require refinement for specific molecular classes to achieve high fidelity.

Purpose of the Study:

• To reparametrize force fields for core molecules across 9 different β-lactam classes.
• To improve the accuracy of dihedral angle parameters for better reproduction of quantum-optimized geometries in MD simulations.

Main Methods:

• Utilized the force field Toolkit and Gaussian calculations for parameterization.
• Focused on optimizing dihedral angle parameters, particularly phase shifts.
• Developed a strategy for predicting phase shifts based on optimized quantum geometry.

Main Results:

• Successfully parameterized 8 out of 11 studied molecules.
• Demonstrated that phase shifts are key to successful dihedral angle parameterization.
• Showed that CGenFF parameters provide a good starting point, but phase shift prediction is critical.

Conclusions:

• Predicting dihedral phase shifts is vital for accurate ligand parameterization in MD simulations.
• The developed strategy offers a simple and effective method for improving force field parameterization of drug-like molecules.
• Enhanced force fields contribute to more reliable computational drug design.