Structure-based prediction of bZIP partnering specificity

J Mol Biol. 2006 Feb 3;355(5):1125-42. doi: 10.1016/j.jmb.2005.11.036. Epub 2005 Dec 1.

Abstract

Predicting protein interaction specificity from sequence is an important goal in computational biology. We present a model for predicting the interaction preferences of coiled-coil peptides derived from bZIP transcription factors that performs very well when tested against experimental protein microarray data. We used only sequence information to build atomic-resolution structures for 1711 dimeric complexes, and evaluated these with a variety of functions based on physics, learned empirical weights or experimental coupling energies. A purely physical model, similar to those used for protein design studies, gave reasonable performance. The results were improved significantly when helix propensities were used in place of a structurally explicit model to represent the unfolded reference state. Further improvement resulted upon accounting for residue-residue interactions in competing states in a generic way. Purely physical structure-based methods had difficulty capturing core interactions accurately, especially those involving polar residues such as asparagine. When these terms were replaced with weights from a machine-learning approach, the resulting model was able to correctly order the stabilities of over 6000 pairs of complexes with greater than 90% accuracy. The final model is physically interpretable, and suggests specific pairs of residues that are important for bZIP interaction specificity. Our results illustrate the power and potential of structural modeling as a method for predicting protein interactions and highlight obstacles that must be overcome to reach quantitative accuracy using a de novo approach. Our method shows unprecedented performance in predicting protein-protein interaction specificity accurately using structural modeling and suggests that predicting coiled-coil interactions generally may be within reach.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Basic-Leucine Zipper Transcription Factors* / chemistry
  • Basic-Leucine Zipper Transcription Factors* / metabolism
  • Mathematics
  • Models, Molecular
  • Models, Theoretical*
  • Protein Denaturation
  • Protein Structure, Secondary*
  • Software

Substances

  • Basic-Leucine Zipper Transcription Factors