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首页> 外文期刊>Journal of Molecular Biology >Residual Structure Accelerates Binding of Intrinsically Disordered ACTR by Promoting Efficient Folding upon Encounter
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Residual Structure Accelerates Binding of Intrinsically Disordered ACTR by Promoting Efficient Folding upon Encounter

机译：残余结构通过在遇到的有效折叠时加速本机上无序的actr的结合

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Intrinsically disordered proteins (IDPs) often fold into stable structures upon specific binding. The roles of residual structure of unbound IDPs in coupling binding and folding have been under much debate. While many studies emphasize the importance of conformational flexibility for IDP recognition, it was recently demonstrated that stabilization the N-terminal helix of intrinsically disordered ACTR accelerated its binding to another IDP, NCBD of the CREB-binding protein. To understand how enhancing ACTR helicity accelerates binding, we derived a series of topology-based coarse-grained models that mimicked various ACTR mutants with increasing helical contents and reproduced their NCBD binding affinities. Molecular dynamics simulations were then performed to sample hundreds of reversible coupled binding and folding transitions. The results show that increasing ACTR helicity does not alter the baseline mechanism of synergistic folding, which continues to follow "extended conformational selection" with multiple stages of selection and induced folding. Importantly, these coarse-grained models, while only calibrated based on binding thermodynamics, recapitulate the observed kinetic acceleration with increasing ACTR helicity. However, the residual helices do not enhance the association kinetics via more efficient seeding of productive collisions. Instead, they allow the nonspecific collision complexes to evolve more efficiently into the final bound and folded state, which is the primary source of accelerated association kinetics. Meanwhile, reduced dissociation kinetics with increasing ACTR helicity can be directly attributed to smaller entropic cost of forming the bound state. Altogether, this study provides important mechanistic insights into how residual structure may modulate thermodynamics and kinetics of IDP interactions. (C) 2018 Elsevier Ltd. All rights reserved.
机译：本质上无序的蛋白质（IDP）通常在特异性结合时折叠成稳定的结构。在耦合结合和折叠耦合结合和折叠方面的残余结构的作用得到了很多争论。虽然许多研究强调了IDP识别的构象灵活性的重要性，但最近证明稳定化本质无序ActR的N-末端螺旋加速其与CREB结合蛋白的另一种IDP的结合。要了解加强Actr螺旋的加速绑定，我们衍生出一系列基于拓扑的粗粒模型，其模仿各种actr突变体，随着螺旋含量的增加并再现其NCBD结合亲和力。然后进行分子动力学模拟以对数百个可逆耦合的粘合和折叠转变进行样本。结果表明，增加的Actr螺旋不改变协同折叠的基线机制，这继续遵循“扩展构象选择”，具有多个选择和诱导的折叠。重要的是，这些粗粒模型，而仅基于绑定热力学校准，重新延长了观察到的动力学加速度随着Actr肝脏的增加。然而，残余螺旋不能通过更有效的生产性碰撞的种子来增强关联动力学。相反，它们允许非特异性碰撞复合物更有效地进化到最终结束和折叠状态，这是加速关联动力学的主要来源。同时，随着Actr螺旋的增加，减少的解离动力学可以直接归因于形成界定状态的较小熵成本。总之，本研究提供了对剩余结构如何调制IDP交互的热力学和动力学的重要机械洞察。 （c）2018年elestvier有限公司保留所有权利。

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