Residual Structure Accelerates Binding of Intrinsically Disordered ACTR by Promoting Efficient Folding upon Encounter
Residual Structure Accelerates Binding of Intrinsically Disordered ACTR by Promoting Efficient Folding upon Encounter
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DOI：
10.1016/j.jmb.2018.12.001
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发表时间：
2019-01-18
影响因子：
5.6
通讯作者：
Chen, Jianhan
中科院分区：
文献类型：
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作者：
Liu, Xiaorong;Chen, Jianlin;Chen, Jianhan
内源性无序蛋白（IDP）通常在特异性结合时折叠成稳定的结构。未结合的IDPs的残基结构在偶联结合和折叠中的作用一直备受争议。虽然许多研究强调构象灵活性对于IDP识别的重要性，但最近证明，稳定化固有无序的ACTR的N-末端螺旋加速了其与另一IDP（CREB结合蛋白的NCBD）的结合。为了了解如何增强ACTR螺旋加速结合，我们推导出一系列基于拓扑结构的粗粒度模型，这些模型模拟了螺旋含量增加的各种ACTR突变体，并再现了它们的NCBD结合亲和力。然后进行分子动力学模拟，以采样数百个可逆耦合结合和折叠转变。结果表明，增加ACTR螺旋度不会改变协同折叠的基线机制，其继续遵循具有多个选择和诱导折叠阶段的“扩展构象选择”。重要的是，这些粗粒度的模型，而仅校准的基础上结合热力学，概括了所观察到的动力学加速与ACTR螺旋度增加。然而，残留的螺旋不增强通过更有效的播种生产性碰撞的关联动力学。相反，它们允许非特异性碰撞复合物更有效地演变成最终的结合和折叠状态，这是加速缔合动力学的主要来源。同时，随着ACTR螺旋度的增加，解离动力学降低可以直接归因于形成结合态的较小熵成本。总之，这项研究提供了重要的机制的见解如何残余结构可能会调节热力学和动力学的IDP相互作用。(C)2018爱思唯尔有限公司版权所有
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.