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How the Dynamics of the Metal-Binding Loop Region Controls the Acid Transition in Cupredoxins

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How the Dynamics of the Metal-Binding Loop Region Controls the Acid Transition in Cupredoxins

Department of Chemical and Geological Sciences, University of Modena and Reggio Emilia, via Campi 183, 41125 Modena, Italy
Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 183, 41125 Modena, Italy
§ Institute for Cell and Molecular Biosciences, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, U.K.
Computational Biomolecular Dynamics Group, Max-Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany
CNR-Nano Institute of Nanoscience, via Campi 213/A, 41125 Modena, Italy
Biochemistry, 2013, 52 (42), pp 7397–7404
DOI: 10.1021/bi400860n
Publication Date (Web): September 24, 2013
Copyright © 2013 American Chemical Society
*Phone: +39 059 2055096. E-mail:


Abstract Image

Many reduced cupredoxins undergo a pH-dependent structural rearrangement, triggered by protonation of the His ligand belonging to the C-terminal hydrophobic loop, usually termed the acid transition. At variance with several members of the cupredoxin family, the acid transition is not observed for azurin (AZ). We have addressed this issue by performing molecular dynamics simulations of AZ and four mutants, in which the C-terminal loop has been replaced with those of other cupredoxins or with polyalanine loops. All of the loop mutants undergo the acid transition in the pH range of 4.4–5.5. The main differences between AZ and its loop mutants are the average value of the active site solvent accessible surface area and the extent of its fluctuations with time, together with an altered structure of the water layer around the copper center. Using functional mode analysis, we found that these variations arise from changes in nonbonding interactions in the second coordination sphere of the copper center, resulting from the loop mutation. Our results strengthen the view that the dynamics at the site relevant for function and its surroundings are crucial for protein activity and for metal-containing electron transferases.


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  • Published In Issue October 22, 2013
  • Article ASAPOctober 14, 2013
  • Just Accepted ManuscriptSeptember 24, 2013
  • Received: July 02, 2013
    Revised: September 23, 2013

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