Systematic Evaluation of ReaxFF Reactive Force Fields for Biochemical Applications

Area of Science:

• Computational chemistry
• Biomolecular modeling
• Force field development

Background:

• ReaxFF force fields are widely used for simulating chemical reactions in biological systems.
• Previous benchmarks have focused on specific aspects or smaller molecular systems.

Purpose of the Study:

• To systematically evaluate the performance of four established ReaxFF force fields on fundamental amino acid and dipeptide systems.
• To identify limitations in current ReaxFF force fields regarding structural, energetic, and reactive properties.

Main Methods:

• Benchmarking four ReaxFF force fields against quantum mechanical calculations for 20 amino acids and 11 dipeptides.
• Analysis of geometries, energetics, atomic charges, and reaction pathways for condensation reactions.

Main Results:

• Systematic errors exceeding 100° in amino acid torsion angles and inaccurate relative conformer energies were observed.
• Only one force field quantitatively reproduced dipeptide formation reaction energies.
• All force fields predicted unphysical reaction mechanisms, including unstable intermediates and five-coordinate carbons.

Conclusions:

• Current ReaxFF force fields, despite training on biochemical systems, exhibit significant deficiencies for amino acids and dipeptide formation.
• The predicted reaction mechanisms and energy landscapes are often unphysical, limiting their reliability for complex biochemical reaction simulations.