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FreeSolv: a database of experimental and calculated hydration free energies, with input files

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Abstract

This work provides a curated database of experimental and calculated hydration free energies for small neutral molecules in water, along with molecular structures, input files, references, and annotations. We call this the Free Solvation Database, or FreeSolv. Experimental values were taken from prior literature and will continue to be curated, with updated experimental references and data added as they become available. Calculated values are based on alchemical free energy calculations using molecular dynamics simulations. These used the GAFF small molecule force field in TIP3P water with AM1-BCC charges. Values were calculated with the GROMACS simulation package, with full details given in references cited within the database itself. This database builds in part on a previous, 504-molecule database containing similar information. However, additional curation of both experimental data and calculated values has been done here, and the total number of molecules is now up to 643. Additional information is now included in the database, such as SMILES strings, PubChem compound IDs, accurate reference DOIs, and others. One version of the database is provided in the Supporting Information of this article, but as ongoing updates are envisioned, the database is now versioned and hosted online. In addition to providing the database, this work describes its construction process. The database is available free-of-charge via http://www.escholarship.org/uc/item/6sd403pz.

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Notes

  1. Obtained using essentially the same protocols.

  2. With one exception described below.

  3. The author selected is usually one of those involved in running the calculations represented; for most of these sets, J. Peter Guthrie was key in determining the composition of the set.

  4. It does contain a variety of carboxylic acids which would be expected to be charged in solution at neutral pH, but hydration free energies of these are typically reported for the neutral form of the molecule.

  5. Tetrahydropyran numbering is used here.

  6. Various groups used extremely long names and were abbreviated, while some other groups which were underrepresented were filtered out. We provide statistics only for groups occurring in more than 5 compounds, and we renamed “tertiary aliphatic amine (trialkylamine)” to “trialkylamine”, “halogen derivative” to “halogenated”, “tertiary aliphatic/aromatic amine (alkylarylamine)” to “alkylarylamine (3rd)”, “primary aliphatic amine (alkylamine)” to “alkyl amine”, “phenol or hydroxyhetarene” to “phenolic”, “secondary aliphatic/aromatic amine (alkylarylamine)” to “alkylarylamine (2nd)”, “secondary aliphatic amine (dialkylamine)” to “dialkylamine”, “orthocarboxylic acid derivative” to “ca-ortho”, and “carboxylic acid ester” to “ca-ester”.

  7. As was the case when we examined the average error in our set by functional group, we simplified and shortened a variety of group names, as well as merging some groups and passing over others which contained too few or too many compounds. Specifically, every “carboxylic acid” was abbreviated “ca”, so “carboxylic acid amidine” became “ca-amidine”, etc. Other names were simplified to aid alphabetizing, such as “primary aliphatic amine (alkylamine)” being replaced by “amine, alkyl”, and similar changes for other alcohols and amines. “carbamic acid ester (urethane)” became “urethane”, and “halogen derivative” became “halogenated”. We otherwise retained only groups which occurred in at least 30 compounds in DrugBank, and passed over groups labeled “aromatic”, “heterocyclic”, “anion”, “cation”, and “alkene” because they tended to hit too many compounds or (in the case of “anion” and “cation”) were assigned in error. Other groups were merged to save space, either because they involved sub-categories (i.e. “carboxylic acid imide, N-unsubstituted” and “carboxylic acid imide, N-substituted” just became “carboxylic acid imide”) or to reduce the number of categories (“acetal” and “hemiacetal” became “acetal or hemiacetal”).

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Acknowledgments

We thank Robert C. Rizzo (Stony Brook University) for help tracking down an issue with hexafluoropropene, and many others who have been involved in work on the experimental and calculated values represented in this database, including Élise Dumont, John D. Chodera, Ken A. Dill, Alan E. Barber, II, Anthony Nicholls, Christopher I. Bayly, Matthew D. Cooper, Vijay S. Pande, Michael R. Shirts, Pavel V. Klimovich, Shuai Liu, David S. Cerutti, William C. Swope, Julia E. Rice, Christopher J. Fennell, Nathan M. Lim, and Karisa L. Wymer. We also appreciate work done by Karisa Wymer and Jessica Fuselier towards initial curation of the set. DLM appreciates financial support from the National Institutes of Health (1R15GM096257-01A1), and computing support from the UCI GreenPlanet cluster, supported in part by NSF Grant CHE-0840513.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences and Department of Chemistry, University of California, 147 Bison Modular, Irvine, CA, 92697, USA

    David L. Mobley

  2. Department of Chemistry, University of New Orleans, 2000 Lakeshore Drive, New Orleans, LA, 70148, USA

    David L. Mobley

  3. Department of Chemistry, University of Western Ontario, London, ON, Canada

    J. Peter Guthrie

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  1. David L. Mobley
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Correspondence to David L. Mobley.

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Mobley, D.L., Guthrie, J.P. FreeSolv: a database of experimental and calculated hydration free energies, with input files. J Comput Aided Mol Des 28, 711–720 (2014). https://doi.org/10.1007/s10822-014-9747-x

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  • DOI: https://doi.org/10.1007/s10822-014-9747-x

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