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

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.

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Acknowledgments

E.G. and R.K.P. acknowledge support from the National Science Foundation (SI2-SSE 1440665). R.M.L. acknowledges support from the National Institutes of Health (GM30580 and P50 GM103368). T.K. acknowledges support from the National Institutes of Health (1R01GM100946 and 5SC3GM095417). L.W. acknowledges support from PSC-CUNY (68457-00 46). REMD simulations were carried out on the Supermic cluster of XSEDE (supported by TG-MCB150001), and BOINC distributed networks at Temple University and Brooklyn College of the City University of New York. The authors acknowledge invaluable technical support from Gene Mayro, Jaykeen Holt, Zachary Hanson-Hart from the IT department at Temple University, and James Roman, and John Stephen at Brooklyn College.

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Correspondence to Emilio Gallicchio.

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The original version of this article was revised: Corrections done in the original article has been published in the erratum.

An erratum to this article is available at http://dx.doi.org/10.1007/s10822-016-9987-z.

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Pal, R.K., Haider, K., Kaur, D. et al. 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 31, 29–44 (2017). https://doi.org/10.1007/s10822-016-9956-6

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Keywords

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