A Fixed-Charge Model for Alcohol Polarization in the Condensed Phase, and Its Role in Small Molecule Hydration

Abstract

We present a simple optimization strategy for incorporating experimental dielectric response information on neat liquids in classical molecular models of alcohol. Using this strategy, we determine simple and transferable hydroxyl modulation rules that, when applied to an existing molecular parameter set, result in a newly dielectric corrected (DC) parameter set. We applied these rules to the general Amber force field (GAFF) to form an initial set of GAFF-DC parameters, and we found this to lead to significant improvement in the calculated dielectric constant and hydration free energy values for a wide variety of small molecule alcohol models. Tests of the GAFF-DC parameters in the SAMPL4 blind prediction event for hydration show these changes improve agreement with experiment. Surprisingly, these simple modifications also outperform detailed quantum mechanical electric field calculations using a self-consistent reaction field environment coupling term. This work provides a potential benchmark for future developments in methods for representing condensed-phase environments in electronic structure calculations.

Evaluation of solvation free energies for small molecules with the AMOEBA polarizable force field

“…This improvement is likely a combination of two factors. First, the GAFF force field, first established in 2004,32 is now a well‐developed and well understood small molecule force field, whose solute parameters (beyond the independently derived point charges) have undergone multiple rounds of refinement and been used in multiple other free energy investigations and blind challenges 21, 27, 31, 70, 71. This extensive history of testing and development is clearly beneficial for GAFF performance, as demonstrated here and in the other recent solvation free energy studies described above.…”

1.14*CM1A-LBCC: Localized Bond-Charge Corrected CM1A Charges for Condensed-Phase Simulations

“…A recent study reported an interesting variant of AM1-BCC charges that reduces some of the over-estimations by reparameterization to reproduce the dielectric constants for pure liquids (GAFF-DC). 8 …”

“…3–5 In spite of recent advances made in the development of polarizable force fields, 6,7 fixed point charge models are still indispensible because of their low computational cost and reasonable accuracy. 8–12 …”

Evaluation of Selected Classical Force Fields for Alchemical Binding Free Energy Calculations of Protein-Carbohydrate Complexes

“…1.5 kcal· mol −1 for alcohols. 76 In saccharides, these errors could be larger due to the greater number of hydroxyl groups present in the structures; compound 6 contains five hydroxyls. The axial group R 1 is always solvent exposed, and the equatorial group R 2 interacts with water in 6α (R 2 = −OH) but makes a hydrogen bond with Tyr37 in 6β (R 2 = −CH 2 OH).…”