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

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dc.contributor.author Zhang, Weihong
dc.contributor.author Ganguly, Debabani
dc.contributor.author Chen, Jianhan
dc.date.accessioned 2012-05-18T13:39:24Z
dc.date.available 2012-05-18T13:39:24Z
dc.date.issued 2012-05-18
dc.identifier.uri http://hdl.handle.net/2097/13834
dc.description.abstract To 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.relation.uri www.ploscompbiol.org en_US
dc.subject Residual structures en_US
dc.subject Conformational fluctuations en_US
dc.subject Intrinsically disordered proteins en_US
dc.subject Electrostatic interactions en_US
dc.title Residual structures, conformational fluctuations, and electrostatic interactions in the synergistic folding of two intrinsically disordered proteins en_US
dc.type Article (publisher version) en_US
dc.date.published 2012 en_US
dc.citation.doi doi:10.1371/journal.pcbi.1002353 en_US
dc.citation.issue 1 en_US
dc.citation.jtitle PLoS Computational Biology en_US
dc.citation.spage e1002353 en_US
dc.citation.volume 8 en_US
dc.contributor.authoreid jiahanc en_US
dc.contributor.authoreid debabani en_US

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