QUASI-ANHARMONIC ANALYSIS REVEALS INTERMEDIATE STATES IN THE NUCLEAR CO-ACTIVATOR RECEPTOR BINDING DOMAIN ENSEMBLE. In: Biocomputing 2012

Book · Thu Dec 01 00:00:00 EST 2011

DOI:https://doi.org/10.1142/9789814366496_0008· OSTI ID:1567618

BURGER, VIRGINIA M. ^[1]; RAMANATHAN, ARVIND ^[2]; SAVOL, ANDREJ J. ^[1]; STANLEY, CHRISTOPHER B. ^[3]; AGARWAL, PRATUL K. ^[2]; CHENNUBHOTLA, CHAKRA S. ^[1]

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1. Department of Computational and Systems Biology, University of Pittsburgh, Pennsylvania 15260, USA
2. Computational Biology Institute and Computer Science and Mathematics Division, USA
3. Neutron Scattering Science Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, USA

The molten globule nuclear receptor co-activator binding domain (NCBD) of CREB binding protein (CBP) selectively recruits transcription co-activators (TCAs) during the formation of the transcription preinitiation complex. NCBD:TCA interactions have been implicated in several cancers, however, the mechanisms of NCBD:TCA recognition remain uncharacterized. NCBD:TCA intermolecular recognition has challenged traditional investigation as both NCBD and several of its corresponding TCAs are intrinsically disordered. Using 40μs of explicit solvent molecular dynamics simulations, we relate the conformational diversity of ligand-free NCBD to its bound configurations. We introduce two novel techniques to quantify the conformational heterogeneity of ligand-free NCBD, dihedral quasi-anharmonic analysis (dQAA) and hierarchical graph-based diffusive clustering. With this integrated approach we find that three of four ligand-bound states are natively accessible to the ligand-free NCBD simulations with root-mean squared deviation (RMSD) less than 2Å These conformations are accessible via diverse pathways while a rate-limiting barrier must be crossed in order to access the fourth bound state.

• Research Organization: Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF)
• Sponsoring Organization: USDOE Office of Science (SC)
• OSTI ID: 1567618
• Country of Publication: United States
• Language: English