Resolving the NFκB Heterodimer Binding Paradox: Strain and Frustration Guide the Binding of Dimeric Transcription Factors

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dc.citation.firstpage18558en_US
dc.citation.issueNumber51en_US
dc.citation.journalTitleJournal of the American Chemical Societyen_US
dc.citation.lastpage18566en_US
dc.citation.volumeNumber139en_US
dc.contributor.authorPotoyan, Davit A.en_US
dc.contributor.authorBueno, Carlosen_US
dc.contributor.authorZheng, Weihuaen_US
dc.contributor.authorKomives, Elizabeth A.en_US
dc.contributor.authorWolynes, Peter G.en_US
dc.date.accessioned2019-12-11T15:44:26Zen_US
dc.date.available2019-12-11T15:44:26Zen_US
dc.date.issued2017en_US
dc.description.abstractMany eukaryotic transcription factors function after forming oligomers. The choice of protein partners is a nonrandom event that has distinct functional consequences for gene regulation. In the present work we examine three dimers of transcription factors in the NFκB family: p50p50, p50p65, and p65p65. The NFκB dimers bind to a myriad of genomic sites and switch the targeted genes on or off with precision. The p65p50 heterodimer of NFκB is the strongest DNA binder, and its unbinding is controlled kinetically by molecular stripping from the DNA induced by IκB. In contrast, the homodimeric forms of NFκB, p50p50 and p65p65, bind DNA with significantly less affinity, which places the DNA residence of the homodimers under thermodynamic rather than kinetic control. It seems paradoxical that the heterodimer should bind more strongly than either of the symmetric homodimers since DNA is a nearly symmetric target. Using a variety of energy landscape analysis tools, here we uncover the features in the molecular architecture of NFκB dimers that are responsible for these drastically different binding free energies. We show that frustration in the heterodimer interface gives the heterodimer greater conformational plasticity, allowing the heterodimer to better accommodate the DNA. We also show how the elastic energy and mechanical strain in NFκB dimers can be found by extracting the principal components of the fluctuations in Cartesian coordinates as well as fluctuations in the space of physical contacts, which are sampled via simulations with a predictive energy landscape Hamiltonian. These energetic contributions determine the specific detailed mechanisms of binding and stripping for both homo- and heterodimers.en_US
dc.identifier.citationPotoyan, Davit A., Bueno, Carlos, Zheng, Weihua, et al.. "Resolving the NFκB Heterodimer Binding Paradox: Strain and Frustration Guide the Binding of Dimeric Transcription Factors." <i>Journal of the American Chemical Society,</i> 139, no. 51 (2017) American Chemical Society: 18558-18566. https://doi.org/10.1021/jacs.7b08741.en_US
dc.identifier.digitalnihms938292en_US
dc.identifier.doihttps://doi.org/10.1021/jacs.7b08741en_US
dc.identifier.urihttps://hdl.handle.net/1911/107858en_US
dc.language.isoengen_US
dc.publisherAmerican Chemical Societyen_US
dc.rightsThis is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by the American Chemical Society.en_US
dc.titleResolving the NFκB Heterodimer Binding Paradox: Strain and Frustration Guide the Binding of Dimeric Transcription Factorsen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpost-printen_US
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