CHARMM fluctuating charge force field for proteins: I parameterization and application to bulk organic liquid...

Area of Science:

• Computational Chemistry
• Molecular Dynamics Simulations
• Force Field Development

Background:

• Accurate molecular simulations require robust force fields that capture condensed phase behavior.
• Existing force fields often struggle to precisely model electrostatic interactions and polarization effects in condensed phases.
• Fluctuating charge (FQ) models offer a promising avenue for improving electrostatic descriptions in molecular simulations.

Purpose of the Study:

• To present a first-generation fluctuating charge (FQ) force field for protein simulations.
• To parameterize the FQ model using quantum mechanical calculations and experimental condensed phase data.
• To evaluate the FQ model's ability to reproduce condensed phase properties and polarization effects.

Main Methods:

• Parameterization of electrostatic model using DFT-based charge responses and a dipolar probe.
• Determination of nonbonded parameters via simultaneous optimization of gas-phase and condensed-phase properties.
• Validation using small organic molecules, pure bulk liquids, and simulations of N-methylacetamide (NMA) in TIP4P-FQ water.

Main Results:

• The FQ model accurately reproduces vacuum solute-water geometries (0.19 Å r.m.s. error) and dimerization energies (0.98 kcal/mol r.m.s. error).
• The model captures condensed phase effects, showing increased molecular dipole moments compared to the gas phase.
• Simulations reveal enhanced dipolar interactions and stronger association in hydrogen-bonding liquids.

Conclusions:

• The developed FQ force field successfully models condensed phase polarization effects.
• The model shows promise for simulating solvated peptide and protein systems.
• Further development and application to complex biological systems are warranted.