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Multimodal Structural Distribution of the p53 C-Terminal Domain upon Binding to S100B via a Generalized Ensemble Method: From Disorder to Extradisorder

  • Shinji Iida
    Shinji Iida
    Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan
    More by Shinji Iida
  • Takeshi Kawabata
    Takeshi Kawabata
    Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan
  • Kota Kasahara
    Kota Kasahara
    College of Life Sciences, Ritsumeikan University, Noji-higashi 1-1-1, Kusatsu, Shiga 525-8577, Japan
  • Haruki Nakamura
    Haruki Nakamura
    Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan
  • , and 
  • Junichi Higo*
    Junichi Higo
    Graduate School of Simulation Studies, University of Hyogo, 7-1-28 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan
    *E-mail: [email protected]
    More by Junichi Higo
Cite this: J. Chem. Theory Comput. 2019, 15, 4, 2597–2607
Publication Date (Web):March 11, 2019
https://doi.org/10.1021/acs.jctc.8b01042
Copyright © 2019 American Chemical Society

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    Abstract

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    Intrinsically disordered regions (IDRs) of a protein employ a flexible binding manner when recognizing a partner molecule. Moreover, it is recognized that binding of IDRs to a partner molecule is accompanied by folding, with a variety of bound conformations often being allowed in formation of the complex. In this study, we investigated a fragment of the disordered p53 C-terminal domain (CTDf) that interacts with one of its partner molecules, S100B, as a representative IDR. Although the 3D structure of CTDf in complex with S100B has been previously reported, the specific interactions remained controversial. To clarify these interactions, we performed generalized ensemble molecular dynamics (MD) simulations (virtual-system coupled multicanonical MD, termed V-McMD), which enable effective conformational sampling beyond that provided by conventional MD. These simulations generated a multimodal structural distribution for our system including CTDf and S100B, indicating that CTDf forms a variety of complex structures upon binding to S100B. We confirmed that our results are consistent with chemical shift perturbations and nuclear Overhauser effects that were observed in previous studies. Furthermore, we calculated the conformational entropy of CTDf in bound and isolated (free) states. Comparison of these CTDf entropies indicated that the disordered CTDf shows further increase in conformational diversity upon binding to S100B. Such entropy gain by binding may comprise an important feature of complex formation for IDRs.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jctc.8b01042.

    • Figure S1; influence of initial conformations on structural ensemble; Figure S2; Figure S3; Table S1; intra-S100B and steric restraints; V-McMD; actual sampling procedure: MD and MC; Figure S4; ensemble reweighting; principal component analysis; Figure S5; parameter estimation for DBSCAN; Figure S6; Table S2; satisfaction ratio of NMR model with upper bounds; Table S3; Figure S7; reconstruction of NMR models; Figure S8; Figure S9; Figure S10; quasi-harmonic conformational entropy; shape of CTDf binding interface on S100B; Figure S11; surface of mSin3 receptor against NRSF disordered peptide; Figure S12; biological implication of multimodal interactions; Figure S13; Figure S14 (PDF)

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    This article is cited by 13 publications.

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