Data-driven prediction and design of bZIP coiled-coil interactions.

TitleData-driven prediction and design of bZIP coiled-coil interactions.
Publication TypeJournal Article
Year of Publication2015
AuthorsPotapov V, Kaplan JB, Keating AE
JournalPLoS Comput Biol
Volume11
Issue2
Paginatione1004046
Date Published2015 Feb
ISSN1553-7358
KeywordsAmino Acid Sequence, Basic-Leucine Zipper Transcription Factors, Computational Biology, Humans, Models, Molecular, Models, Statistical, Peptides, Protein Multimerization, Protein Structure, Secondary
Abstract

Selective dimerization of the basic-region leucine-zipper (bZIP) transcription factors presents a vivid example of how a high degree of interaction specificity can be achieved within a family of structurally similar proteins. The coiled-coil motif that mediates homo- or hetero-dimerization of the bZIP proteins has been intensively studied, and a variety of methods have been proposed to predict these interactions from sequence data. In this work, we used a large quantitative set of 4,549 bZIP coiled-coil interactions to develop a predictive model that exploits knowledge of structurally conserved residue-residue interactions in the coiled-coil motif. Our model, which expresses interaction energies as a sum of interpretable residue-pair and triplet terms, achieves a correlation with experimental binding free energies of R = 0.68 and significantly out-performs other scoring functions. To use our model in protein design applications, we devised a strategy in which synthetic peptides are built by assembling 7-residue native-protein heptad modules into new combinations. An integer linear program was used to find the optimal combination of heptads to bind selectively to a target human bZIP coiled coil, but not to target paralogs. Using this approach, we designed peptides to interact with the bZIP domains from human JUN, XBP1, ATF4 and ATF5. Testing more than 132 candidate protein complexes using a fluorescence resonance energy transfer assay confirmed the formation of tight and selective heterodimers between the designed peptides and their targets. This approach can be used to make inhibitors of native proteins, or to develop novel peptides for applications in synthetic biology or nanotechnology.

DOI10.1371/journal.pcbi.1004046
Alternate JournalPLoS Comput. Biol.
PubMed ID25695764
PubMed Central IDPMC4335062
Grant ListGM067681 / GM / NIGMS NIH HHS / United States
T32 GM007287 / GM / NIGMS NIH HHS / United States