The nuclear receptor co-activator binding domain (NCBD) of CREB binding protein (CBP) selectively recruits transcription co-activators (TCAs) such as steroid-receptor co-activator-1 (SRC-1) and interferon regulatory factor-3 (IRF-3), all of which are implicated in cancer. NCBD forms highly specific amphipathic helical bundles (a1-a3) with each TCA albeit with differing helical topologies. Elucidating the biophysical mechanisms of how NCBD adapts its binding surface to each TCA is challenging because NCBD is intrinsically disordered existing as a molten globule under physiological conditions and is known to undergo synergistic folding upon binding. To understand how NCBD binds to various TCAs, we probed the conformational diversity of the apo- and holo-forms of NCBD using all-atom, explicit solvent molecular dynamics simulations (~40 �s) and small-angle neutron scattering experiments (~hours). To bridge the gap between experimental time-scales and computational details, we propose a multi-scale approach called anharmonic conformational analysis (ACA). ACA reveals a hierarchy of conformational sub-states and intermediates that play a key role in NCBD:TCA recognition. In contrast to previous implicit solvent simulations, our study reveals the presence of a rare sub-state (<4% of overall population), where NCBD resembles its TCA complexed form, with backbone root-mean squared deviations < 2 � for SRC-1 and < 4 � for IRF-3. Further, the specificity-binding loop in NCBD adopts intermediate conformations that enable the bending and twisting of a1 and a2 into its final orientation with the target TCA. By analyzing the motions of surface waters, we also show how the solvent enables NCBD retain its molten globule form and yet adopt highly diverse conformations. Taken together, our multi-scale modeling of the NCBD conformational landscape provides novel insights into the biophysical mechanisms of molecular recognition in intrinsically disordered proteins.

Multiscale modeling reveals the recognition specificity of the intrinsically disordered nuclear co-activator binding domain (NCBD)

244th National Meeting (2012)

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