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Binding of Cations and Protons in the Active Site of Acetylcholinesterase

  • Conference paper
Modelling of Biomolecular Structures and Mechanisms

Part of the book series: The Jerusalem Symposia on Quantum Chemistry and Biochemistry ((JSQC,volume 27))

Abstract

The active site of acetylcholinesterase contains a number of ionizable residues. The pK as of the catalytic histidine, His 440, is believed to be 6.3, based upon enzyme kinetic studies. However, the pK as of the other residues have not been measured. Here, we describe calculations of the pK a of the ionizable groups in this enzyme. Interestingly, the initial calculations predict a pK a of 9.3 for His 440. The deviation of 3 pK a units from the measured pK a is traceable to the influence of Glu 199 and Glu 443 upon His 440. We argue that the deviation does not represent a failure of the computational method. Rather it points to the need for an adjustment in the model of the protein. The adjustment we suggest involves a monovalent cation bound in the active site, near Glu 199 and His 440. Including such a cation in the calculations brings the computed pK a of His 440 into agreement with the measured value. Furthermore, the idea that a bound cation substantially reduces tbe pK a of His 440 leads to satisfying explanations of a number of otherwise puzzling experimental data.

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Author information

Authors and Affiliations

  1. Department of Chemistry, University of Houston, Houston, TX, 77204-5641, USA

    Stanislaw T. Wlodek, Jan Antosiewicz, Andrew McCammon & Michael K. Gilson

  2. Dept. of Biophysics, University of Warsaw, 02-089, Warsaw, Poland

    Stanislaw T. Wlodek & Jan Antosiewicz

  3. Center for Advanced Research in Biotechnology, 9600 Gudelsky Drive, Rockville, MD, 20850, USA

    Stanislaw T. Wlodek

Authors
  1. Stanislaw T. Wlodek
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  2. Jan Antosiewicz
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  3. Andrew McCammon
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  4. Michael K. Gilson
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Editor information

Editors and Affiliations

  1. Fondation Edmond de Rothschild, Institut de Biologie Physico-Chimique, Paris, France

    A. Pullman  & B. Pullman  & 

  2. The Israel Academy of Sciences and Humanities, Jerusalem, Israel

    J. Jortner

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© 1995 Springer Science+Business Media Dordrecht

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Wlodek, S.T., Antosiewicz, J., McCammon, A., Gilson, M.K. (1995). Binding of Cations and Protons in the Active Site of Acetylcholinesterase. In: Pullman, A., Jortner, J., Pullman, B. (eds) Modelling of Biomolecular Structures and Mechanisms. The Jerusalem Symposia on Quantum Chemistry and Biochemistry, vol 27. Springer, Dordrecht. https://doi.org/10.1007/978-94-011-0497-5_3

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  • DOI: https://doi.org/10.1007/978-94-011-0497-5_3

  • Publisher Name: Springer, Dordrecht

  • Print ISBN: 978-94-010-4222-2

  • Online ISBN: 978-94-011-0497-5

  • eBook Packages: Springer Book Archive

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