Parametrization of Force Field Bonded Terms under Structural Inconsistency

Area of Science:

• Computational Chemistry
• Molecular Modeling
• Drug Discovery

Background:

• Molecular mechanics (MM) force fields (FFs) are crucial for simulating molecular systems.
• Current FF parametrization relies on fitting quantum mechanical (QM) data, often leading to suboptimal parameters when MM and QM geometries diverge.
• Incremental parametrization procedures can introduce inaccuracies due to transferred parameters.

Purpose of the Study:

• To develop and validate a novel method for deriving MM force field parameters that accounts for structural deviations.
• To improve the accuracy and transferability of bond and angle parameters in FFs for small molecules.
• To enhance the reproduction of QM normal mode frequencies using the new parametrization approach.

Main Methods:

• Developed a new parametrization method based on potential energy surface scans, explicitly allowing structural deviations between QM and MM optimized geometries.
• Tested the new method on a diverse set of 32 small molecules.
• Evaluated the robustness and transferability of the derived bond and angle parameters.

Main Results:

• The new method successfully generates robust and transferable bond and angle parameters without additional restraints.
• It significantly improves the agreement of normal mode frequencies compared to conventional methods.
• Average error in reproducing QM normal mode frequencies reduced from 9.5% (CGenFF) to 6.8% with the new parameters.

Conclusions:

• The developed method offers a superior approach for parametrizing MM force fields, particularly for small molecules where structural deviations are common.
• It yields more accurate and transferable parameters, enhancing the reliability of molecular simulations.
• This advancement facilitates more precise molecular modeling and aids in drug discovery applications.