Assessing the quality of absolute hydration free energies among CHARMM-compatible ligand parameterization schemes

Abstract

Multipurpose atom-typer for CHARMM (MATCH), an atom-typing toolset for molecular mechanics force fields, was recently developed in our laboratory. Here, we assess the ability of MATCH-generated parameters and partial atomic charges to reproduce experimental absolute hydration free energies for a series of 457 small neutral molecules in GBMV2, Generalized Born with a smooth SWitching (GBSW), and fast analytical continuum treatment of solvation (FACTS) implicit solvent models. The quality of hydration free energies associated with small molecule parameters obtained from ParamChem, SwissParam, and Antechamber are compared. Given optimized surface tension coefficients for scaling the surface area term in the nonpolar contribution, these automated parameterization schemes with GBMV2 and GBSW demonstrate reasonable agreement with experimental hydration free energies (average unsigned errors of 0.9-1.5 kcal/mol and R(2) of 0.63-0.87). GBMV2 and GBSW consistently provide slightly more accurate estimates than FACTS, whereas Antechamber parameters yield marginally more accurate estimates than the current generation of MATCH, ParamChem, and SwissParam parameterization strategies. Modeling with MATCH libraries that are derived from different CHARMM topology and parameter files highlights the importance of having sufficient coverage of chemical space within the underlying databases of these automated schemes and the benefit of targeting specific functional groups for parameterization efforts to maximize both the breadth and the depth of the parameterized space.

Figure 1

Schematic of the compounds whose partial charge distributions in ParamChem resulted in a molecular dipole difference of more than 0.01 Debye compared to the partial charge assignments in CGENFF. For clarity, only atoms whose ParamChem charges were more than 0.01 e⁻ from CGENFF are labeled. Note: MATCH(cgenff) charges essentially reproduce the CGENFF charges for these compounds so are not labeled.

Figure 2

Average unsigned errors of hydration free energies by chemical class for four different parameterization schemes in the GBMV2 implicit solvent model for the A) 82 molecules that are in CGENFF and B) the 375 compounds that are not included in CGENFF.

Figure 3

Average unsigned errors of hydration free energies for specific chemical classes for (top panel) CGENFF molecules and (bottom panel) non-CGENFF compounds. Classes in which A) both MATCH(cgenff) and ParamChem have AUEs for the non-CGENFF set more than 1 kcal/mol worse than the CGENFF set; B) MATCH(cgenff) performs 1 kcal/mol better or worse than ParamChem; C) SwissParam performs more than 1 kcal/mol poorer than the other force fields; and D) both MATCH(cgenff) and ParamChem perform more than 1 kcal/mol poorer than either SwissParam or GAFF/AM1-BCC.

Figure 4

Average unsigned errors of hydration free energies by chemical class for the MATCH(cgenff) and MATCH(combined) parameterization schemes in the GBMV2 implicit solvent model for the A) 73 molecules that are in CGENFF and B) the 277 compounds that are not included in CGENFF.