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Resolving the problem of trapped water in binding cavities : prediction of host–guest binding free energies in the SAMPL5 challenge by funnel metadynamics

Bhakat, Soumendranath LU and Söderhjelm, Pär LU (2017) In Journal of Computer-Aided Molecular Design p.119-132
Abstract

The funnel metadynamics method enables rigorous calculation of the potential of mean force along an arbitrary binding path and thereby evaluation of the absolute binding free energy. A problem of such physical paths is that the mechanism characterizing the binding process is not always obvious. In particular, it might involve reorganization of the solvent in the binding site, which is not easily captured with a few geometrically defined collective variables that can be used for biasing. In this paper, we propose and test a simple method to resolve this trapped-water problem by dividing the process into an artificial host-desolvation step and an actual binding step. We show that, under certain circumstances, the contribution from the... (More)

The funnel metadynamics method enables rigorous calculation of the potential of mean force along an arbitrary binding path and thereby evaluation of the absolute binding free energy. A problem of such physical paths is that the mechanism characterizing the binding process is not always obvious. In particular, it might involve reorganization of the solvent in the binding site, which is not easily captured with a few geometrically defined collective variables that can be used for biasing. In this paper, we propose and test a simple method to resolve this trapped-water problem by dividing the process into an artificial host-desolvation step and an actual binding step. We show that, under certain circumstances, the contribution from the desolvation step can be calculated without introducing further statistical errors. We apply the method to the problem of predicting host–guest binding free energies in the SAMPL5 blind challenge, using two octa-acid hosts and six guest molecules. For one of the hosts, well-converged results are obtained and the prediction of relative binding free energies is the best among all the SAMPL5 submissions. For the other host, which has a narrower binding pocket, the statistical uncertainties are slightly higher; longer simulations would therefore be needed to obtain conclusive results.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Binding free energy, Host–guest complex, MD simulation, Metadynamics, SAMPL5
in
Journal of Computer-Aided Molecular Design
pages
119 - 132
publisher
Kluwer
external identifiers
  • scopus:84984649642
  • wos:000392326500010
ISSN
0920-654X
DOI
10.1007/s10822-016-9948-6
language
English
LU publication?
yes
id
27da0dd2-a262-4187-b7eb-29c329b28e68
date added to LUP
2016-12-01 09:26:51
date last changed
2018-02-11 04:24:22
@article{27da0dd2-a262-4187-b7eb-29c329b28e68,
  abstract     = {<p>The funnel metadynamics method enables rigorous calculation of the potential of mean force along an arbitrary binding path and thereby evaluation of the absolute binding free energy. A problem of such physical paths is that the mechanism characterizing the binding process is not always obvious. In particular, it might involve reorganization of the solvent in the binding site, which is not easily captured with a few geometrically defined collective variables that can be used for biasing. In this paper, we propose and test a simple method to resolve this trapped-water problem by dividing the process into an artificial host-desolvation step and an actual binding step. We show that, under certain circumstances, the contribution from the desolvation step can be calculated without introducing further statistical errors. We apply the method to the problem of predicting host–guest binding free energies in the SAMPL5 blind challenge, using two octa-acid hosts and six guest molecules. For one of the hosts, well-converged results are obtained and the prediction of relative binding free energies is the best among all the SAMPL5 submissions. For the other host, which has a narrower binding pocket, the statistical uncertainties are slightly higher; longer simulations would therefore be needed to obtain conclusive results.</p>},
  author       = {Bhakat, Soumendranath and Söderhjelm, Pär},
  issn         = {0920-654X},
  keyword      = {Binding free energy,Host–guest complex,MD simulation,Metadynamics,SAMPL5},
  language     = {eng},
  pages        = {119--132},
  publisher    = {Kluwer},
  series       = {Journal of Computer-Aided Molecular Design},
  title        = {Resolving the problem of trapped water in binding cavities : prediction of host–guest binding free energies in the SAMPL5 challenge by funnel metadynamics},
  url          = {http://dx.doi.org/10.1007/s10822-016-9948-6},
  year         = {2017},
}