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. 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

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Free PMC article

A Combined Treatment of Hydration and Dynamical Effects for the Modeling of Host-Guest Binding Thermodynamics: The SAMPL5 Blinded Challenge

Rajat Kumar Pal et al. J Comput Aided Mol Des. .
Free PMC article

Erratum in

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.

Figures

Fig. 1
Fig. 1
Location of hydration sites within the binding cavity of the hosts as identified from hydration site analysis. a Octa-acid, b methyl octa-acid, c CB-clip
Fig. 2
Fig. 2
a Position of the hydration spheres added to AGBNP2 parameters for each hosts, b the carbon atoms used to position the hydration sphere in all three hosts; the carbon atoms marked in magenta are used for positioning the water sites on the top cavity of octa-acids; in CB-clip, those carbons are used to position water site in between two naphthalene rings; the center of masses of carbons marked in green were used to position water-sites in the middle cavity of the octa-acids; carbons marked in orange were used to model a water site at the bottom cavity of the octa-acids; in CB-clip, a water site is positioned at the center of mass of those four carbons
Fig. 3
Fig. 3
Calculated standard binding free energies from the SAMPL5 octa-acid (a), methyl octa-acid (b) and CB-clip (c) complexes against the corresponding experimental values. The points in green filled circles are the binding free energies obtained with the incorporation of salt effects. Filled black triangles are the free energies obtained without salt effects. RMSE = Root Mean-Squared Error, r = Pearson correlation coefficient
Fig. 4
Fig. 4
Representative structures from the simulations of the complexes with the octa-acid with a the negatively charged guest 1 (without flipping of the benzoate ring), and b with the positively charged guest 3 showing the flipping of the benzoate ring to form a short-ranged ionic interaction with the alkylammonium head group of the ligand. c Representative structure of the complex of the methyl octa-acid host with guest 4 showing the methyl benzoate rings forced upwards to accommodate the bulky ligand

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