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The denatured state of HIV-1 protease under native conditions
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  • Heike Rösner,
  • Martina Caldarini,
  • Gregory Potel,
  • Daniel Malmodin,
  • Maria Vanoni,
  • Alessandro Aliverti,
  • Ricardo Broglia,
  • Birthe Kragelund,
  • Guido Tiana
Heike Rösner
University of Copenhagen

Corresponding Author:hir@bio.ku.dk

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Martina Caldarini
University of Milano
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Gregory Potel
Lawrence Livermore National Laboratory
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Daniel Malmodin
University of Copenhagen
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Maria Vanoni
University of Milan
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Alessandro Aliverti
Universita degli Studi di Milano
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Ricardo Broglia
University of Milan
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Birthe Kragelund
University of Copenhagen
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Guido Tiana
University of Milan
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Abstract

The denatured state of several proteins has been shown to display transient structures that are relevant for folding, stability and aggregation. To detect them by nuclear magnetic resonance (NMR) spectroscopy, the denatured state must be stabilized by chemical agents or changes in temperature. This makes the environment different from that experienced in biologically relevant processes. Using high-resolution heteronuclear NMR spectroscopy, we have characterized several denatured states of a monomeric variant of HIV-1 protease induced by different concentrations of urea, guanidinium chloride and acetic acid. We have extrapolated the chemical shifts and the relaxation parameters to the denaturant-free denatured state at native conditions, showing that they converge to the same values. Subsequently, we characterized the conformational properties of this biologically relevant denatured state under native conditions by advanced molecular dynamics simulations and validated the results by comparison to experimental data. We show that the denatured state of HIV-1 protease under native conditions displays rich patterns of transient native and non-native structures, which could be of relevance to its guidance through a complex folding process.
10 Jun 2021Submitted to PROTEINS: Structure, Function, and Bioinformatics
18 Jun 2021Submission Checks Completed
18 Jun 2021Assigned to Editor
18 Jun 2021Reviewer(s) Assigned
19 Jul 2021Review(s) Completed, Editorial Evaluation Pending
20 Jul 2021Editorial Decision: Revise Minor
20 Jul 20211st Revision Received
22 Jul 2021Submission Checks Completed
22 Jul 2021Assigned to Editor
22 Jul 2021Review(s) Completed, Editorial Evaluation Pending
22 Jul 2021Editorial Decision: Accept
03 Aug 2021Published in Proteins: Structure, Function, and Bioinformatics. 10.1002/prot.26189