Comparison of enveloping distribution sampling and thermodynamic integration to calculate binding free energies of phenylethanolamine N-methyltransferase inhibitors

Riniker, Sereina, Christ, Clara D., Hansen, Niels, Mark, Alan E., Nair, Pramod C. and van Gunsteren, Wilfred F. (2011) Comparison of enveloping distribution sampling and thermodynamic integration to calculate binding free energies of phenylethanolamine N-methyltransferase inhibitors. Journal of Chemical Physics, 135 2: 024105.1-024105.13. doi:10.1063/1.3604534

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Author Riniker, Sereina
Christ, Clara D.
Hansen, Niels
Mark, Alan E.
Nair, Pramod C.
van Gunsteren, Wilfred F.
Title Comparison of enveloping distribution sampling and thermodynamic integration to calculate binding free energies of phenylethanolamine N-methyltransferase inhibitors
Journal name Journal of Chemical Physics   Check publisher's open access policy
ISSN 0021-9606
1089-7690
1520-9032
Publication date 2011-07-14
Sub-type Article (original research)
DOI 10.1063/1.3604534
Open Access Status File (Publisher version)
Volume 135
Issue 2
Start page 024105.1
End page 024105.13
Total pages 13
Place of publication College Park, MD, U.S.A.
Publisher American Institute of Physics
Collection year 2012
Language eng
Formatted abstract
The relative binding free energy between two ligands to a specific protein can be obtained using various computational methods. The more accurate and also computationally more demanding techniques are the so-called free energy methods which use conformational sampling from molecular dynamics or Monte Carlo simulations to generate thermodynamic averages. Two such widely applied methods are the thermodynamic integration (TI) and the recently introduced enveloping distribution sampling (EDS) methods. In both cases relative binding free energies are obtained through the alchemical perturbations of one ligand into another in water and inside the binding pocket of the protein. TI requires many separate simulations and the specification of a pathway along which the system is perturbed from one ligand to another. Using the EDS approach, only a single automatically derived reference state enveloping both end states needs to be sampled. In addition, the choice of an optimal pathway in TI calculations is not trivial and a poor choice may lead to poor convergence along the pathway. Given this, EDS is expected to be a valuable and computationally efficient alternative to TI. In this study, the performances of these two methods are compared using the binding of ten tetrahydroisoquinoline derivatives to phenylethanolamine N-transferase as an example. The ligands involve a diverse set of functional groups leading to a wide range of free energy differences. In addition, two different schemes to determine automatically the EDS reference state parameters and two different topology approaches are compared.
Keyword Molecular-dynamics simulations
Single simulation
Biomolecular simulation
State
Site
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
School of Chemistry and Molecular Biosciences
 
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