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Analysis of 15N–1H NMR Relaxation in Proteins by a Combined Experimental and Molecular Dynamics Simulation Approach: Picosecond–Nanosecond Dynamics of the Rho GTPase Binding Domain of Plexin-B1 in the Dimeric State Indicates Allosteric Pathways

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    Analysis of 15N–1H NMR Relaxation in Proteins by a Combined Experimental and Molecular Dynamics Simulation Approach: Picosecond–Nanosecond Dynamics of the Rho GTPase Binding Domain of Plexin-B1 in the Dimeric State Indicates Allosteric Pathways
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    † Dipartimento di Scienze Chimiche, Università degli Studi di Padova, Padova 35131, Italy
    ‡ Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106-7169, United States
    § Methodologie RMN, Faculté des Sciences et Techniques, Nancy-Université, Nancy 54500, France
    The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel
    *E-mail: [email protected] (E.M.); [email protected] (M.B.).
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    The Journal of Physical Chemistry B

    Cite this: J. Phys. Chem. B 2013, 117, 1, 174–184
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    https://doi.org/10.1021/jp310142f
    Published December 7, 2012
    Copyright © 2012 American Chemical Society
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    Abstract

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    We investigate picosecond–nanosecond dynamics of the Rho-GTPase Binding Domain (RBD) of plexin-B1, which plays a key role in plexin-mediated cell signaling. Backbone 15N relaxation data of the dimeric RBD are analyzed with the model-free (MF) method, and with the slowly relaxing local structure/molecular dynamics (SRLS-MD) approach. Independent analysis of the MD trajectories, based on the MF paradigm, is also carried out. MF is a widely popular and simple method, SRLS is a general approach, and SRLS-MD is an integrated approach we developed recently. Corresponding parameters from the RBD dimer, a previously studied RBD monomer mutant, and the previously studied complex of the latter with the GTPase Rac1, are compared. The L2, L3, and L4 loops of the plexin-B1 RBD are involved in interactions with other plexin domains, GTPase binding, and RBD dimerization, respectively. Peptide groups in the loops of both the monomeric and dimeric RBD are found to experience weak and moderately asymmetric local ordering centered approximately at the Ci–1α–Ciα axes, and nanosecond backbone motion. Peptide groups in the α-helices and the β-strands of the dimer (the β-strands of the monomer) experience strong and highly asymmetric local ordering centered approximately at the Ci–1α–Ciα axes (N–H bonds). N–H fluctuations occur on the picosecond time scale. An allosteric pathway for GTPase binding, providing new insights into plexin function, is delineated.

    Copyright © 2012 American Chemical Society

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    Supporting Information

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    A section showing the algebraic relation between S2, on the one hand, and S02 and S22, on the other hand. A paragraph delineating the MF models featured by the computer program Dynamics. (48) A figure showing the experimental 15N T1, T2 and 15N–{1H} NOE values for the dimer acquired at 14.1 and 18.8 T. A figure showing 4 MD trajectories for the plexin dimer. A figure showing S2 and τe from MF and MD. A table summarizing the parameters used in the MD simulations. A table showing the experimental 15N T1, T2 and 15N–{1H} NOE values for the dimer acquired at 14.1 and 18.8 T. A table showing the best-fit vlues of S2 and τe obtained with MF analysis. A table showing the best-fit values of S02, S22, c02, and c22 obtained from MD analysis. A table showing the best-fit values of D2,∥, D2,⊥, αO, βO, αD, and βD obtained with SRLS-based data-fitting (in most cases, the angles αO, βO and αD have been pre-set to −90°) analysis. This material is available free of charge via the Internet at http://pubs.acs.org.

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    The Journal of Physical Chemistry B

    Cite this: J. Phys. Chem. B 2013, 117, 1, 174–184
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jp310142f
    Published December 7, 2012
    Copyright © 2012 American Chemical Society
    Request reuse permissions

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