Links between the charge model and bonded parameter force constants in biomolecular force fields.

Area of Science:

• Computational chemistry and molecular modeling.
• Development and validation of biomolecular force fields.

Background:

• The ff15ipq protein force field utilizes a fixed charge model with dual charge sets for bonded parameter derivation (gas phase) and simulations (aqueous solution).
• This approach aims to account for water-induced electronic polarization, but the phase-specific fitting data requires careful consideration.

Purpose of the Study:

• To compare the standard ff15ipq force field with two alternative parameterization strategies: ff15ipq-Qsolv (solution phase charges for bonded parameters) and ff15ipq-Vac (vacuum phase charges for simulations).
• To evaluate the impact of phase-specific fitting data on the accuracy of protein and peptide simulations.

Main Methods:

• Development of ff15ipq-Qsolv and ff15ipq-Vac using automated tools and expanded datasets.
• Simulation of globular proteins (e.g., Trp cage, villin, lysozyme, GB3) and short peptides (5-19 residues).
• Analysis of protein stability, secondary structure content (e.g., helical character), and free energy surfaces.

Main Results:

• Both ff15ipq and ff15ipq-Qsolv depict stable globular proteins.
• ff15ipq-Qsolv improves helical content modeling in some systems but overestimates it in others and promotes helix formation in disordered peptides, suggesting potential bias.
• ff15ipq-Vac inaccurately predicts globular protein unfolding and shows no improvement over ff15ipq or ff15ipq-Qsolv for short peptides.

Conclusions:

• The IPolQ charge model and its associated protocol represent an incremental improvement when phase-specific fitting data is considered.
• ff15ipq-Qsolv's parameter development strategy may introduce systematic bias, potentially explaining the need for manual corrections in force field evolution.
• ff15ipq-Vac demonstrates significant limitations in modeling protein stability, highlighting the importance of consistent phase treatment in force field development.