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Interpretation of NMR relaxation properties of Pin1, a two-domain protein, based on Brownian dynamic simulations

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Abstract

Many important proteins contain multiple domains connected by flexible linkers. Inter-domain motion is suggested to play a key role in many processes involving molecular recognition. Heteronuclear NMR relaxation is sensitive to motions in the relevant time scales and could provide valuable information on the dynamics of multi-domain proteins. However, the standard analysis based on the separation of global tumbling and fast local motions is no longer valid for multi-domain proteins undergoing internal motions involving complete domains and that take place on the same time scale than the overall motion.

The complexity of the motions experienced even for the simplest two-domain proteins are difficult to capture with simple extensions of the classical Lipari–Szabo approach. Hydrodynamic effects are expected to dominate the motion of the individual globular domains, as well as that of the complete protein. Using Pin1 as a test case, we have simulated its motion at the microsecond time scale, at a reasonable computational expense, using Brownian Dynamic simulations on simplified models. The resulting trajectories provide insight on the interplay between global and inter-domain motion and can be analyzed using the recently published method of isotropic Reorientational Mode Dynamics which offer a way of calculating their contribution to heteronuclear relaxation rates. The analysis of trajectories computed with Pin1 models of different flexibility provides a general framework to understand the dynamics of multi-domain proteins and explains some of the observed features in the relaxation rate profile of free Pin1.

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Author notes

  1. Pau Bernadó

    Present address: Institut de Biologie Structurale, Jean Pierre Ebel, 41 rue Jules Horowitz, 38027, Grenoble Cedex, France

  2. Klaus Fiebig

    Present address: Affinium Pharmaceuticals, 100 University Ave., 12th Floor North Tower, Toronto, Ontario, M5J 1V6, Canada

Authors and Affiliations

  1. Departament de Química Orgànica, Universitat de Barcelona, Martí i Franquès 1-11, 08028, Barcelona, Spain

    Pau Bernadó

  2. Laboratori de RMN de Biomolècules, Parc Científic de Barcelona, Josep Samitier 1-5, 08028, Barcelona, Spain

    Miquel Pons

  3. Departamento de Química Física, Facultad de Química, Universidad de Murcia, 30071, Múrcia, Spain

    Miguel X. Fernandes & José García de la Torre

  4. Institut für Organische Chemie und Chemische Biologie, Johann Wolfgang Goethe-Universität Frankfurt, Marie-Curie Str. 11, 60439, Frankfurt, Germany

    Doris M. Jacobs & Klaus Fiebig

Authors
  1. Pau Bernadó
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  2. Miguel X. Fernandes
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  3. Doris M. Jacobs
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  4. Klaus Fiebig
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  5. José García de la Torre
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  6. Miquel Pons
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Correspondence to Miquel Pons.

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Bernadó, P., Fernandes, M.X., Jacobs, D.M. et al. Interpretation of NMR relaxation properties of Pin1, a two-domain protein, based on Brownian dynamic simulations. J Biomol NMR 29, 21–35 (2004). https://doi.org/10.1023/B:JNMR.0000019499.60777.6e

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  • DOI: https://doi.org/10.1023/B:JNMR.0000019499.60777.6e

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