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Molecular dynamics simulation of β2-microglobulin in denaturing and stabilizing conditions

Authors

  • Federico Fogolari,

    Corresponding author
    1. Dipartimento di Scienze e Tecnologie Biomediche, Universita' di Udine, Piazzale Kolbe 4, 33100 Udine, Italy
    2. Istituto Nazionale Biostrutture e Biosistemi, Viale medaglie d'Oro 305 - 00136 Roma, Italy
    • Dipartimento di Scienze e Tecnologie Biomediche, Universita' di Udine, Piazzale Kolbe 4, 33100 Udine, Italy
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  • Alessandra Corazza,

    1. Dipartimento di Scienze e Tecnologie Biomediche, Universita' di Udine, Piazzale Kolbe 4, 33100 Udine, Italy
    2. Istituto Nazionale Biostrutture e Biosistemi, Viale medaglie d'Oro 305 - 00136 Roma, Italy
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  • Nicola Varini,

    1. CINECA, Via Magnanelli 6/3, 40033 Casalecchio di Reno (BO), Italy
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  • Matteo Rotter,

    1. Dipartimento di Scienze e Tecnologie Biomediche, Universita' di Udine, Piazzale Kolbe 4, 33100 Udine, Italy
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  • Devrim Gumral,

    1. Dipartimento di Scienze e Tecnologie Biomediche, Universita' di Udine, Piazzale Kolbe 4, 33100 Udine, Italy
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    • Devrim Gumral current address is Department of Genetics and Bioengineering, Yeditepe University, Atasehir, 34755 Istanbul, Turkey

  • Luca Codutti,

    1. Dipartimento di Scienze e Tecnologie Biomediche, Universita' di Udine, Piazzale Kolbe 4, 33100 Udine, Italy
    2. Istituto Nazionale Biostrutture e Biosistemi, Viale medaglie d'Oro 305 - 00136 Roma, Italy
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  • Enrico Rennella,

    1. Dipartimento di Scienze e Tecnologie Biomediche, Universita' di Udine, Piazzale Kolbe 4, 33100 Udine, Italy
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  • Paolo Viglino,

    1. Dipartimento di Scienze e Tecnologie Biomediche, Universita' di Udine, Piazzale Kolbe 4, 33100 Udine, Italy
    2. Istituto Nazionale Biostrutture e Biosistemi, Viale medaglie d'Oro 305 - 00136 Roma, Italy
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  • Vittorio Bellotti,

    1. Istituto Nazionale Biostrutture e Biosistemi, Viale medaglie d'Oro 305 - 00136 Roma, Italy
    2. Dipartimento di Biochimica, Università di Pavia, Laboratori di Biotecnologie, IRCCS Policlinico San Matteo, via Taramelli 3b, I-27100 Pavia, Italy
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  • Gennaro Esposito

    1. Dipartimento di Scienze e Tecnologie Biomediche, Universita' di Udine, Piazzale Kolbe 4, 33100 Udine, Italy
    2. Istituto Nazionale Biostrutture e Biosistemi, Viale medaglie d'Oro 305 - 00136 Roma, Italy
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Abstract

β2-Microglobulin has been a model system for the study of fibril formation for 20 years. The experimental study of β2-microglobulin structure, dynamics, and thermodynamics in solution, at atomic detail, along the pathway leading to fibril formation is difficult because the onset of disorder and aggregation prevents signal resolution in Nuclear Magnetic Resonance experiments. Moreover, it is difficult to characterize conformers in exchange equilibrium. To gain insight (at atomic level) on processes for which experimental information is available at molecular or supramolecular level, molecular dynamics simulations have been widely used in the last decade. Here, we use molecular dynamics to address three key aspects of β2-microglobulin, which are known to be relevant to amyloid formation: (1) 60 ns molecular dynamics simulations of β2-microglobulin in trifluoroethanol and in conditions mimicking low pH are used to study the behavior of the protein in environmental conditions that are able to trigger amyloid formation; (2) adaptive biasing force molecular dynamics simulation is used to force cis-trans isomerization at Proline 32 and to calculate the relative free energy in the folded and unfolded state. The native-like trans-conformer (known as intermediate 2 and determining the slow phase of refolding), is simulated for 10 ns, detailing the possible link between cis-trans isomerization and conformational disorder; (3) molecular dynamics simulation of highly concentrated doxycycline (a molecule able to suppress fibril formation) in the presence of β2-microglobulin provides details of the binding modes of the drug and a rationale for its effect. Proteins 2011. © 2010 Wiley-Liss, Inc.

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