Chen Jianhan
Department of Biochemistry, Kansas State University, Manhattan, Kansas 66506, USA.
J Am Chem Soc. 2009 Feb 18;131(6):2088-9. doi: 10.1021/ja809547p.
Intrinsically disordered proteins (IDPs) are functional proteins where a lack of stable tertiary structures is required for function. Many of the IDPs involved in cellular regulation and signaling have substantial residual structures in the unbound state and fold into stable structures upon binding to their biological partners. Specific roles of these residual structures in and the underlying mechanisms of coupled binding and folding are poorly understood. Here we use physics-based atomistic simulations to compute the multidimensional free energy surfaces of coupled folding and binding of the intrinsically disordered p53 extreme C-terminus to protein S100B(betabeta). The results show that, even though the unbound p53 peptide appears to sample several alternative folded states previously observed when in complex with various targets, it binds to S100B(betabeta) through formation of nonspecific complexes, i.e., a "fly-casting"-like process. The current work, together with previous NMR and coarse-grained modeling studies of another prototypical system, suggests that the main role of the residual structures in the unbound states of regulatory IDPs might be to provide thermodynamic control of binding through modulating the entropic cost of folding and not to enhance the binding rate by acting as initial contact sites.
内在无序蛋白（IDPs）是一类功能性蛋白质，其功能的实现需要缺乏稳定的三级结构。许多参与细胞调控和信号传导的IDPs在未结合状态下具有大量的残余结构，并在与生物伴侣结合时折叠成稳定结构。这些残余结构在结合和折叠过程中的具体作用以及潜在机制尚不清楚。在此，我们使用基于物理的原子模拟来计算内在无序的p53极端C末端与蛋白质S100B（ββ）耦合折叠和结合的多维自由能表面。结果表明，尽管未结合的p53肽似乎采样了先前与各种靶标结合时观察到的几种替代折叠状态，但它通过形成非特异性复合物，即类似“抛蝇钓”的过程与S100B（ββ）结合。当前的工作，连同之前对另一个典型系统的核磁共振和粗粒度建模研究表明，调控性IDPs未结合状态下残余结构的主要作用可能是通过调节折叠的熵成本来提供对结合的热力学控制，而不是通过作为初始接触位点来提高结合速率。
