Combining the polarizable Drude force field with a continuum electrostatic Poisson-Boltzmann implicit solvation...

Area of Science:

• Computational chemistry
• Molecular modeling
• Biophysics

Background:

• Accurate prediction of solvation free energies is crucial for molecular simulations.
• Additive force fields often neglect polarization effects, limiting their accuracy.
• Developing improved models for solvation is an ongoing challenge in computational chemistry.

Purpose of the Study:

• To develop and validate a novel polarizable force field model combining the Drude oscillator with a Poisson-Boltzmann/solvent-accessible surface area (PB/SASA) approach.
• To assess the model's performance in reproducing experimental solvation free energies and relative binding free energies.
• To evaluate the contribution of polarization work to the total solvation free energy.

Main Methods:

• Parameterization of a Drude oscillator-based polarizable force field coupled with a continuum PB/SASA model.
• Self-consistent optimization of Drude particle positions within the solvent reaction field.
• Validation against experimental solvation free energies of small molecules and relative binding free energies of protein mutations.

Main Results:

• The Drude PB/SASA model achieved a root mean square difference of 0.8 kcal/mol for solvation free energies of 70 molecules, significantly better than the CHARMM36 force field (2.5 kcal/mol).
• Polarization work was identified as a significant contributor to solvation free energy, comparable to polar interactions.
• The model yielded a root mean square deviation of 3.35 kcal/mol for relative binding free energies, outperforming CHARMM36 (5.11 kcal/mol).

Conclusions:

• The Drude PB/SASA model offers a significant improvement over additive force fields for calculating solvation and binding free energies.
• The model accurately captures electronic polarization effects in both small molecules and proteins.
• The primary limitation identified is the solvent-accessible surface area (SASA) component's accuracy in representing non-polar solvation effects.