Prediction of volatile anesthetic binding sites in proteins

John H. Streiff, Thomas W. Allen, Elena Atanasova, Nenad Juranic, Slobodan I Macura, Alan R. Penheiter, Keith A. Jones

Research output: Contribution to journalArticle

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Abstract

Computational methods designed to predict and visualize ligand protein binding interactions were used to characterize volatile anesthetic (VA) binding sites and unoccupied pockets within the known structures of VAs bound to serum albumin, luciferase, and apoferritin. We found that both the number of protein atoms and methyl hydrogen, which are within ∼8 Å of a potential ligand binding site, are significantly greater in protein pockets where VAs bind. This computational approach was applied to structures of calmodulin (CaM), which have not been determined in complex with a VA. It predicted that VAs bind to [Ca2+]4-CaM, but not to apo-CaM, which we confirmed with isothermal titration calorimetry. The VA binding sites predicted for the structures of [Ca2+]4-CaM are located in hydrophobic pockets that form when the Ca2+ binding sites in CaM are saturated. The binding of VAs to these hydrophobic pockets is supported by evidence that halothane predominantly makes contact with aliphatic resonances in [Ca 2+]4-CaM (nuclear Overhauser effect) and increases the Ca2+ affinity of CaM (fluorescence spectroscopy). Our computational analysis and experiments indicate that binding of VA to proteins is consistent with the hydrophobic effect and the Meyer-Overton rule.

Original languageEnglish (US)
Pages (from-to)3405-3414
Number of pages10
JournalBiophysical Journal
Volume91
Issue number9
DOIs
StatePublished - Nov 2006

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Calmodulin
Anesthetics
Binding Sites
Proteins
Apoferritins
Ligands
Calorimetry
Fluorescence Spectrometry
Halothane
Luciferases
Protein Binding
Serum Albumin
Hydrogen

ASJC Scopus subject areas

  • Biophysics

Cite this

Streiff, J. H., Allen, T. W., Atanasova, E., Juranic, N., Macura, S. I., Penheiter, A. R., & Jones, K. A. (2006). Prediction of volatile anesthetic binding sites in proteins. Biophysical Journal, 91(9), 3405-3414. https://doi.org/10.1529/biophysj.106.082586

Prediction of volatile anesthetic binding sites in proteins. / Streiff, John H.; Allen, Thomas W.; Atanasova, Elena; Juranic, Nenad; Macura, Slobodan I; Penheiter, Alan R.; Jones, Keith A.

In: Biophysical Journal, Vol. 91, No. 9, 11.2006, p. 3405-3414.

Research output: Contribution to journalArticle

Streiff, JH, Allen, TW, Atanasova, E, Juranic, N, Macura, SI, Penheiter, AR & Jones, KA 2006, 'Prediction of volatile anesthetic binding sites in proteins', Biophysical Journal, vol. 91, no. 9, pp. 3405-3414. https://doi.org/10.1529/biophysj.106.082586
Streiff JH, Allen TW, Atanasova E, Juranic N, Macura SI, Penheiter AR et al. Prediction of volatile anesthetic binding sites in proteins. Biophysical Journal. 2006 Nov;91(9):3405-3414. https://doi.org/10.1529/biophysj.106.082586
Streiff, John H. ; Allen, Thomas W. ; Atanasova, Elena ; Juranic, Nenad ; Macura, Slobodan I ; Penheiter, Alan R. ; Jones, Keith A. / Prediction of volatile anesthetic binding sites in proteins. In: Biophysical Journal. 2006 ; Vol. 91, No. 9. pp. 3405-3414.
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