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J Comput Chem. 2011 Oct;32(13):2909-23. doi: 10.1002/jcc.21876. Epub 2011 Jul 6.

Surveying implicit solvent models for estimating small molecule absolute hydration free energies.

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1
Department of Chemistry, University of Michigan, 930 N. University Ave., Ann Arbor, Michigan 48109, USA.

Abstract

Implicit solvent models are powerful tools in accounting for the aqueous environment at a fraction of the computational expense of explicit solvent representations. Here, we compare the ability of common implicit solvent models (TC, OBC, OBC2, GBMV, GBMV2, GBSW, GBSW/MS, GBSW/MS2 and FACTS) to reproduce experimental absolute hydration free energies for a series of 499 small neutral molecules that are modeled using AMBER/GAFF parameters and AM1-BCC charges. Given optimized surface tension coefficients for scaling the surface area term in the nonpolar contribution, most implicit solvent models demonstrate reasonable agreement with extensive explicit solvent simulations (average difference 1.0-1.7 kcal/mol and R(2)=0.81-0.91) and with experimental hydration free energies (average unsigned errors=1.1-1.4 kcal/mol and R(2)=0.66-0.81). Chemical classes of compounds are identified that need further optimization of their ligand force field parameters and others that require improvement in the physical parameters of the implicit solvent models themselves. More sophisticated nonpolar models are also likely necessary to more effectively represent the underlying physics of solvation and take the quality of hydration free energies estimated from implicit solvent models to the next level.

PMID:
21735452
PMCID:
PMC3142295
DOI:
10.1002/jcc.21876
[Indexed for MEDLINE]
Free PMC Article
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