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Pal RK , Haider K , Kaur D , Flynn W , Xia J , Levy RM , Taran T , Wickstrom L , Kurtzman T , Gallicchio E
A combined treatment of hydration and dynamical effects for the modeling of host-guest binding thermodynamics: the SAMPL5 blinded challenge
J Comput Aided Mol Des. 2017 Jan;31(1) :29-44
PMID: 27696239    PMCID: PMC5477994   
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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-Huckel 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.
1573-4951 Pal, Rajat Kumar Haider, Kamran Kaur, Divya Flynn, William Xia, Junchao Levy, Ronald M Taran, Tetiana Wickstrom, Lauren Kurtzman, Tom Gallicchio, Emilio ORCID: http://orcid.org/0000-0002-2606-4913 P50 GM103368/GM/NIGMS NIH HHS/United States R01 GM030580/GM/NIGMS NIH HHS/United States R01 GM100946/GM/NIGMS NIH HHS/United States SC3 GM095417/GM/NIGMS NIH HHS/United States Journal Article Netherlands J Comput Aided Mol Des. 2017 Jan;31(1):29-44. doi: 10.1007/s10822-016-9956-6. Epub 2016 Sep 30.