Recognition Mechanism Of Intrinsical Disordered Proteins

Intrinsically disordered proteins (IDPs) do not sustain spontaneouslywell-folded structures without stable interactions. They are widely existedin cells and display various functions, including molecular recognition,chemical modifications and chaperone. The flexibility of their structures iscontributing to the binding between IDPs and their targets withthermodynamic benefits. However, the recognition mechanism betweenIDPs is still poorly understood. Here we use molecular dynamics (MD)simulations to study the folding mechanism between intrinsic unstructuredprotein p53and cyclic-AMP response element binding protein (CBP). Thenuclear coactivator binding domain (NCBD) of CBP can interact with thetransactivation domain (TAD) of tumor suppressor p53to activatetranscription. NMR experiments show that both apo-TAD and NCBD areintrinsically disordered and they undergo conformational transitions toform structured complex. Both the average RMSD values between bound and apo-NCBD and TAD and Kolmogorov-Smirnov hypothesis testdemonstrate that local NCBD and TAD may obey induced fit mechanism.Quantitative analysis shows that conformational selection may dominateglobal recognition between NCBD and TAD. Furthermore, unfoldingkinetics and energy landscape analysis both support NCBD and TAD mayfollow local induced fit and global conformational selection forrecognition. All methods can be used to analyze other IDPs for molecularrecognition mechanisms.