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

J Chem Theory Comput. 2019 Apr 9;15(4):2597-2607. doi: 10.1021/acs.jctc.8b01042. Epub 2019 Mar 22.


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.

MeSH terms

  • Animals
  • Entropy
  • Humans
  • Intrinsically Disordered Proteins / chemistry
  • Intrinsically Disordered Proteins / metabolism*
  • Molecular Dynamics Simulation
  • Protein Binding
  • Protein Conformation
  • Protein Interaction Domains and Motifs
  • Rats
  • S100 Calcium Binding Protein beta Subunit / chemistry
  • S100 Calcium Binding Protein beta Subunit / metabolism*
  • Thermodynamics
  • Tumor Suppressor Protein p53 / chemistry
  • Tumor Suppressor Protein p53 / metabolism*


  • Intrinsically Disordered Proteins
  • S100 Calcium Binding Protein beta Subunit
  • Tumor Suppressor Protein p53