Exploration of the activation pathway of Δα-Chymotrypsin with molecular dynamics simulations and correlation with kinetic experiments.

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  • Additional Information
    • Publication Year:
      2008
    • Author-Supplied Keywords:
      Conformational changes
      Fluorescence stopped flow
      Kinetics
      Molecular dynamics
      Multiple simulations
      Targeted molecular dynamics
    • Abstract:
      Correlating the experimentally observed kinetics of protein conformational changes with theoretical predictions is a formidable and challenging task, due to the multitude of degrees of freedom (>5,000) in a protein and the huge gap between the timescale of the kinetic event of interest (ms) and the typical timescale of computer simulations (ns). In this study we show that using the targeted molecular dynamics (TMD) method it is possible to simulate conformational changes of the ms time range and to correlate multiple simulations of single pathways with ensemble experiments on both the structural and energetic basis. As a model system we chose to study the conformational change of rat-Δα-chymotrypsin from its inactive to its active conformation. This activation process has been analyzed previously by experimental and theoretical methods, i.e. fluorescence stopped-flow spectroscopy (FSF), molecular dynamics (MD) and TMD. Inspired by the results of these studies on the wild type (WT) enzyme, several mutants were constructed to alter the conformational pathway and studied by FSF measurements. In the present work WT and mutant N18G were subjected to multiple MD and subsequent TMD simulations. We report the existence of two main activation pathways, a feature of chymotrypsin activation that has been hitherto unknown. A method to correlate the energetics of the different pathways calculated by TMD and the kinetic parameters observed by experimental methods such as FSF is presented. Our work is relevant for experimental single molecule studies of enzymes in general. [ABSTRACT FROM AUTHOR]
    • Abstract:
      Copyright of European Biophysics Journal is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
    • ISSN:
      01757571
    • Accession Number:
      34982823
  • Citations
    • ABNT:
      MÄTRAI, J. et al. Exploration of the activation pathway of Δα-Chymotrypsin with molecular dynamics simulations and correlation with kinetic experiments. European Biophysics Journal, [s. l.], v. 38, n. 1, p. 13, 2008. Disponível em: http://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=edb&AN=34982823. Acesso em: 6 jul. 2020.
    • AMA:
      Mätrai J, Jonckheer A, Joris E, et al. Exploration of the activation pathway of Δα-Chymotrypsin with molecular dynamics simulations and correlation with kinetic experiments. European Biophysics Journal. 2008;38(1):13. http://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=edb&AN=34982823. Accessed July 6, 2020.
    • AMA11:
      Mätrai J, Jonckheer A, Joris E, et al. Exploration of the activation pathway of Δα-Chymotrypsin with molecular dynamics simulations and correlation with kinetic experiments. European Biophysics Journal. 2008;38(1):13. Accessed July 6, 2020. http://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=edb&AN=34982823
    • APA:
      Mätrai, J., Jonckheer, A., Joris, E., Krüger, P., Carpenter, E., Tuszynski, J., De Maeyer, M., & Engelborghs, Y. (2008). Exploration of the activation pathway of Δα-Chymotrypsin with molecular dynamics simulations and correlation with kinetic experiments. European Biophysics Journal, 38(1), 13.
    • Chicago/Turabian: Author-Date:
      Mätrai, Janka, Abel Jonckheer, Eddy Joris, Peter Krüger, Eric Carpenter, Jack Tuszynski, Marc De Maeyer, and Yves Engelborghs. 2008. “Exploration of the Activation Pathway of Δα-Chymotrypsin with Molecular Dynamics Simulations and Correlation with Kinetic Experiments.” European Biophysics Journal 38 (1): 13. http://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=edb&AN=34982823.
    • Harvard:
      Mätrai, J. et al. (2008) ‘Exploration of the activation pathway of Δα-Chymotrypsin with molecular dynamics simulations and correlation with kinetic experiments’, European Biophysics Journal, 38(1), p. 13. Available at: http://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=edb&AN=34982823 (Accessed: 6 July 2020).
    • Harvard: Australian:
      Mätrai, J, Jonckheer, A, Joris, E, Krüger, P, Carpenter, E, Tuszynski, J, De Maeyer, M & Engelborghs, Y 2008, ‘Exploration of the activation pathway of Δα-Chymotrypsin with molecular dynamics simulations and correlation with kinetic experiments’, European Biophysics Journal, vol. 38, no. 1, p. 13, viewed 6 July 2020, .
    • MLA:
      Mätrai, Janka, et al. “Exploration of the Activation Pathway of Δα-Chymotrypsin with Molecular Dynamics Simulations and Correlation with Kinetic Experiments.” European Biophysics Journal, vol. 38, no. 1, Nov. 2008, p. 13. EBSCOhost, search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=edb&AN=34982823.
    • Chicago/Turabian: Humanities:
      Mätrai, Janka, Abel Jonckheer, Eddy Joris, Peter Krüger, Eric Carpenter, Jack Tuszynski, Marc De Maeyer, and Yves Engelborghs. “Exploration of the Activation Pathway of Δα-Chymotrypsin with Molecular Dynamics Simulations and Correlation with Kinetic Experiments.” European Biophysics Journal 38, no. 1 (November 2008): 13. http://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=edb&AN=34982823.
    • Vancouver/ICMJE:
      Mätrai J, Jonckheer A, Joris E, Krüger P, Carpenter E, Tuszynski J, et al. Exploration of the activation pathway of Δα-Chymotrypsin with molecular dynamics simulations and correlation with kinetic experiments. European Biophysics Journal [Internet]. 2008 Nov [cited 2020 Jul 6];38(1):13. Available from: http://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=edb&AN=34982823