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J Comput Aided Mol Des. 2017 Jan;31(1):29-44. doi: 10.1007/s10822-016-9956-6. Epub 2016 Sep 30.

A combined treatment of hydration and dynamical effects for the modeling of host-guest binding thermodynamics: the SAMPL5 blinded challenge.

Author information

1
Department of Chemistry, Brooklyn College, 2900 Bedford Avenue, Brooklyn, New York, 11210, USA.
2
Ph.D. Program in Biochemistry, The Graduate Center of the City University of New York, New York, NY, 10016, USA.
3
Department of Chemistry, Lehman College, The City University of New York, 250 Bedford Park Blvd. West, Bronx, New York, NY, 10468, USA.
4
Ph.D. Program in Chemistry, The Graduate Center of the City University of New York, New York, NY, 10016, USA.
5
Center for Biophysics and Computational Biology, Institute of Computational Molecular Science and Department of Chemistry, Temple University, Philadelphia, PA, USA.
6
Department of Physics and Astronomy, Rutgers University, Piscataway, NJ, 08854, USA.
7
Borough of Manhattan Community College, Department of Science, The City University of New York, 199 Chambers Street, New York, NY, 10007, USA.
8
Department of Chemistry, Brooklyn College, 2900 Bedford Avenue, Brooklyn, New York, 11210, USA. egallicchio@brooklyn.cuny.edu.
9
Ph.D. Program in Biochemistry, The Graduate Center of the City University of New York, New York, NY, 10016, USA. egallicchio@brooklyn.cuny.edu.
10
Ph.D. Program in Chemistry, The Graduate Center of the City University of New York, New York, NY, 10016, USA. egallicchio@brooklyn.cuny.edu.

Abstract

As part of the SAMPL5 blinded experiment, we computed the absolute binding free energies of 22 host-guest complexes employing a novel approach based on the BEDAM single-decoupling alchemical free energy protocol with parallel replica exchange conformational sampling and the AGBNP2 implicit solvation model specifically customized to treat the effect of water displacement as modeled by the Hydration Site Analysis method with explicit solvation. Initial predictions were affected by the lack of treatment of ionic charge screening, which is very significant for these highly charged hosts, and resulted in poor relative ranking of negatively versus positively charged guests. Binding free energies obtained with Debye-Hückel treatment of salt effects were in good agreement with experimental measurements. Water displacement effects contributed favorably and very significantly to the observed binding affinities; without it, the modeling predictions would have grossly underestimated binding. The work validates the implicit/explicit solvation approach employed here and it shows that comprehensive physical models can be effective at predicting binding affinities of molecular complexes requiring accurate treatment of conformational dynamics and hydration.

KEYWORDS:

AGBNP2; BEDAM; Debye–Hückel; Hydration Site Analysis (HSA); SAMPL5; Salt effects

PMID:
27696239
PMCID:
PMC5477994
DOI:
10.1007/s10822-016-9956-6
[Indexed for MEDLINE]
Free PMC Article

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