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Abstract
We present a comprehensive study investigating the potential gain in accuracy for calculating absolute solvation free energies (ASFE) using a neural network potential to describe the intramolecular energy of the solute. We calculated the ASFE for most compounds from the FreeSolv database using the Open Force Field (OpenFF) and compared them to earlier results obtained with the CHARMM General Force Field (CGenFF). By applying a nonequilibrium (NEQ) switching approach between the molecular mechanics (MM) description (either OpenFF or CGenFF) and the neural net potential (NNP)/MM level of theory (using ANI-2x as the NNP potential), we attempted to improve the accuracy of the calculated ASFEs. The predictive performance of the results did not change when applying this approach to all 589 small molecules in the FreeSolv database that ANI-2x can describe. When selecting a subset of 156 molecules, focusing on compounds where the force fields performed poorly, we saw a slight improvement in the root-mean-square error (RMSE) and mean absolute error (MAE). The majority of our calculations utilized unidirectional NEQ protocols based on Jarzynski's equation. Additionally, we conducted bidirectional NEQ switching for the subset of 156 solutes. Notably, only a small fraction (10 out of 156) exhibited statistically significant discrepancies between unidirectional and bidirectional NEQ switching free energy estimates.
Supplementary materials
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Supplementary material to the main manuscript
Description
We describe in detail how ASFEs were calculated on the MM level of theory and how the endstate corrections to the ANI-2x potential were applied for the two respective protocols (UVIE and EXS). In Figure S1 we show the error distribution of the MM calculated ASFEs for three different force fields. Figure S2 is the counterpart of Figure 5 of the main manuscript for protocol EXS. In Figure S3 we show several characteristics of the 10 compounds (of the 156 subset), for which the MM -> ML/MM correction differed by more than 1 kT when computed by Jarzynski's and Crooks' equation.
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Title
Full results for 589 compounds from the FreeSolv database
Description
The ASFE on the MM and ML/MM level for the 589 compounds of the FreeSolv database calculated using protocol EXS are summarized
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Detailed results for the 156 compound subset
Description
The ASFE values on the MM and ML/MM level for the two force fields (OpenFF and CGenFF) for the 156 compounds of the combined dataset calculated with protocol EXS and UVIE are summarized. In the case of the correction for CGenFF, unidirectional values are indicated with "Jar", while bidirectional values are depicted with "Crooks"
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Supplementary weblinks
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Notebook to create plots
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The notebook also contains the calculations of all statistics reported in this paper (RMSE, MAE, Pearson correlation, and Spearman's rank correlation) and the corresponding bootstrapped errors.
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View Title
Addon to OpenMM to carry out and post-process non-equilibrium switches
Description
Python code developed specifically for this work (release v0.3)
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