Scientific article
Open access

Pushing the size limit of de novo structure ensemble prediction guided by sparse SDSL-EPR restraints to 200 residues: The monomeric and homodimeric forms of BAX

Published inJournal of structural biology, vol. 195, no. 1, p. 62-71
Publication date2016-07

Structure determination remains a challenge for many biologically important proteins. In particular, proteins that adopt multiple conformations often evade crystallization in all biologically relevant states. Although computational de novo protein folding approaches often sample biologically relevant conformations, the selection of the most accurate model for different functional states remains a formidable challenge, in particular, for proteins with more than about 150 residues. Electron paramagnetic resonance (EPR) spectroscopy can obtain limited structural information for proteins in well-defined biological states and thereby assist in selecting biologically relevant conformations. The present study demonstrates that de novo folding methods are able to accurately sample the folds of 192-residue long soluble monomeric Bcl-2-associated X protein (BAX). The tertiary structures of the monomeric and homodimeric forms of BAX were predicted using the primary structure as well as 25 and 11 EPR distance restraints, respectively. The predicted models were subsequently compared to respective NMR/X-ray structures of BAX. EPR restraints improve the protein-size normalized root-mean-square-deviation (RMSD100) of the most accurate models with respect to the NMR/crystal structure from 5.9 Å to 3.9 Å and from 5.7 Å to 3.3 Å, respectively. Additionally, the model discrimination is improved, which is demonstrated by an improvement of the enrichment from 5% to 15% and from 13% to 21%, respectively.

  • Ab initio
  • DEER
  • EPR
  • Protein structure
  • Protein structure prediction
Affiliation Not a UNIGE publication
  • National Science Foundation - Analytical and Computational Studies of High-Speed Flows in Single-and Multi-Phase Reacting Media [0312040]
  • NIH - [R01 GM099842]
  • NIGMS NIH HHS - [R01 GM080403]
  • Office of Science of the U.S. Department of Energy - [DE-AC05-00OR22725]
  • NSF - [CHE 1305874]
  • NIDDK NIH HHS - [R01 DK097376]
  • Max Planck Society -
Citation (ISO format)
FISCHER, Axel W. et al. Pushing the size limit of <i>de novo</i> structure ensemble prediction guided by sparse SDSL-EPR restraints to 200 residues: The monomeric and homodimeric forms of BAX. In: Journal of structural biology, 2016, vol. 195, n° 1, p. 62–71. doi: 10.1016/j.jsb.2016.04.014
Main files (2)
Article (Accepted version)
Article (Published version)
ISSN of the journal1047-8477

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