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Prediction of Absolute Solvation Free Energies using Molecular Dynamics Free Energy Perturbation and the OPLS Force Field
Abstract
The accurate prediction of protein-ligand binding free energies is a primary objective in computer-aided drug design. The solvation free energy of a small molecule provides a surrogate to the desolvation of the ligand in the thermodynamic process of protein-ligand binding. Here, we use explicit solvent molecular dynamics free energy perturbation to predict the absolute solvation free energies of a set of 239 small molecules, spanning diverse chemical functional groups commonly found in drugs and drug-like molecules. We also compare the performance of absolute solvation free energies obtained using the OPLS_2005 force field with two other commonly used small molecule force fields-general AMBER force field (GAFF) with AM1-BCC charges and CHARMm-MSI with CHelpG charges. Using the OPLS_2005 force field, we obtain high correlation with experimental solvation free energies (R(2) = 0.94) and low average unsigned errors for a majority of the functional groups compared to AM1-BCC/GAFF or CHelpG/CHARMm-MSI. However, OPLS_2005 has errors of over 1.3 kcal/mol for certain classes of polar compounds. We show that predictions on these compound classes can be improved by using a semiempirical charge assignment method with an implicit bond charge correction.
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Metadata
- Authors
- Shivakumar, D., Williams, J., Wu, Y., Damm, W., Shelley, J., & Sherman, W.
- Venue
- Journal of Chemical Theory and Computation
- Publisher
- American Chemical Society (ACS)
- Published
- 2010-04-14
- Volume
- 6
- Issue
- 5
- Pages
- 1509-1519
- ISSN
- 1549-9618 (ISSN-L)
- 1549-9626
- OpenAlex
- W2021832765
- Cited by
- 1,936
- References
- 0
- FWCI
- 26.88
- Type
- journal article
- Language
- en
- Open access
- closed
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