Abstract：
Intrinsically disordered proteins (IDPs) lack a well-defined tertiary structure but are essential players in various biological processes. Their ability to undergo a disorder-to-order transition upon binding to their partners, known as the folding-upon-binding process, is crucial for their function. One classical example is the intrinsically disordered transactivation domain (TAD) of the tumor suppressor protein p53, which quickly forms a structured α-helix after binding to its partner MDM2, with clinical significance for cancer treatment. However, the contribution of nonnative interactions between the IDP and its partner to the rapid binding kinetics, as well as their interplay with native interactions, is not well understood at the atomic level. Here, we used molecular dynamics simulation and Markov state model (MSM) analysis to study the folding-upon-binding mechanism between p53-TAD and MDM2. Our results suggest that the system progresses from the nascent encounter complex to the well-structured encounter complex and finally reaches the native complex, following an induced-fit mechanism. We found that nonnative hydrophobic and hydrogen bond interactions, combined with native interactions, effectively stabilize the nascent and well-structured encounter complexes. Among the nonnative interactions, Leu25p53-Leu54MDM2 and Leu25p53-Phe55MDM2 are particularly noteworthy, as their interaction strength is close to the optimum. Evidently, strengthening or weakening these interactions could both adversely affect the binding kinetics. Overall, our findings suggest that nonnative interactions are evolutionarily optimized to accelerate the binding kinetics of IDPs in conjunction with native interactions.
摘要：
固有无序蛋白质（IDP）缺乏明确的三级结构，但在各种生物过程中是必不可少的参与者。他们在与伴侣结合后经历无序过渡的能力，被称为装订时折叠过程，对他们的功能至关重要。一个典型的例子是肿瘤抑制蛋白p53的内在无序的反式激活域（TAD），它在与其伴侣MDM2结合后迅速形成结构化的α-螺旋，对癌症治疗具有临床意义。然而,IDP与其伴侣之间的非天然相互作用对快速结合动力学的贡献，以及它们与原生互动的相互作用，在原子层面上没有很好的理解。这里,我们使用分子动力学模拟和马尔可夫状态模型（MSM）分析来研究p53-TAD和MDM2之间的折叠结合机制。我们的结果表明，系统从新生的相遇复合体发展到结构良好的相遇复合体，最后到达原生复合体，遵循诱导配合机制。我们发现非天然的疏水和氢键相互作用，结合本地交互，有效地稳定新生和结构良好的相遇复合体。在非本地互动中，Leu25p53-Leu54MDM2和Leu25p53-Phe55MDM2特别值得注意，因为它们的相互作用强度接近最佳值。显然,加强或削弱这些相互作用都会对结合动力学产生不利影响。总的来说,我们的研究结果表明,非天然相互作用是进化优化的,以加速IDPs与天然相互作用的结合动力学.
