Residual structures, conformational fluctuations, and electrostatic interactions in the synergistic folding of two intrinsically disordered proteins

dc.citation.doidoi:10.1371/journal.pcbi.1002353en_US
dc.citation.issue1en_US
dc.citation.jtitlePLoS Computational Biologyen_US
dc.citation.spagee1002353en_US
dc.citation.volume8en_US
dc.contributor.authorZhang, Weihong
dc.contributor.authorGanguly, Debabani
dc.contributor.authorChen, Jianhan
dc.contributor.authoreidjianhancen_US
dc.contributor.authoreiddebabanien_US
dc.date.accessioned2012-05-18T13:39:24Z
dc.date.available2012-05-18T13:39:24Z
dc.date.issued2012-05-18
dc.date.published2012en_US
dc.description.abstractTo understand the interplay of residual structures and conformational fluctuations in the interaction of intrinsically disordered proteins (IDPs), we first combined implicit solvent and replica exchange sampling to calculate atomistic disordered ensembles of the nuclear co-activator binding domain (NCBD) of transcription coactivator CBP and the activation domain of the p160 steroid receptor coactivator ACTR. The calculated ensembles are in quantitative agreement with NMRderived residue helicity and recapitulate the experimental observation that, while free ACTR largely lacks residual secondary structures, free NCBD is a molten globule with a helical content similar to that in the folded complex. Detailed conformational analysis reveals that free NCBD has an inherent ability to substantially sample all the helix configurations that have been previously observed either unbound or in complexes. Intriguingly, further high-temperature unbinding and unfolding simulations in implicit and explicit solvents emphasize the importance of conformational fluctuations in synergistic folding of NCBD with ACTR. A balance between preformed elements and conformational fluctuations appears necessary to allow NCBD to interact with different targets and fold into alternative conformations. Together with previous topology-based modeling and existing experimental data, the current simulations strongly support an ‘‘extended conformational selection’’ synergistic folding mechanism that involves a key intermediate state stabilized by interaction between the C-terminal helices of NCBD and ACTR. In addition, the atomistic simulations reveal the role of long-range as well as short-range electrostatic interactions in cooperating with readily fluctuating residual structures, which might enhance the encounter rate and promote efficient folding upon encounter for facile binding and folding interactions of IDPs. Thus, the current study not only provides a consistent mechanistic understanding of the NCBD/ACTR interaction, but also helps establish a multi-scale molecular modeling framework for understanding the structure, interaction, and regulation of IDPs in general.en_US
dc.identifier.urihttp://hdl.handle.net/2097/13834
dc.relation.uriwww.ploscompbiol.orgen_US
dc.subjectResidual structuresen_US
dc.subjectConformational fluctuationsen_US
dc.subjectIntrinsically disordered proteinsen_US
dc.subjectElectrostatic interactionsen_US
dc.titleResidual structures, conformational fluctuations, and electrostatic interactions in the synergistic folding of two intrinsically disordered proteinsen_US
dc.typeArticle (publisher version)en_US

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