Burger Virginia M, Ramanathan Arvind, Savol Andrej J, Stanley Christopher B, Agarwal Pratul K, Chennubhotla Chakra S
Joint Carnegie Mellon University-University of Pittsburgh PhD Program in Computational Biology, Pittsburgh, Pennsylvania, USA.
Pac Symp Biocomput. 2012:70-81.
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.
CREB结合蛋白（CBP）的熔融球状核受体共激活因子结合结构域（NCBD）在转录起始前复合物形成过程中选择性募集转录共激活因子（TCA）。NCBD与TCA的相互作用与多种癌症有关，然而，NCBD与TCA识别的机制仍未明确。由于NCBD及其一些相应的TCA本质上都是无序的，NCBD与TCA的分子间识别对传统研究提出了挑战。通过40微秒的显式溶剂分子动力学模拟，我们将无配体NCBD的构象多样性与其结合构型联系起来。我们引入了两种新技术来量化无配体NCBD的构象异质性，即二面角准非谐分析（dQAA）和基于层次图的扩散聚类。通过这种综合方法，我们发现无配体NCBD模拟中四个配体结合状态中的三个在天然状态下是可及的，均方根偏差（RMSD）小于2Å。这些构象可通过多种途径获得，而要获得第四个结合状态则必须跨越一个限速屏障。
