Mechanism of Folding and Binding of an Intrinsically Disordered Protein As Revealed by ab Initio Simulations
Mechanism of Folding and Binding of an Intrinsically Disordered Protein As Revealed by ab Initio Simulations
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DOI：
10.1021/ct500287c
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发表时间：
2014-06-01
影响因子：
5.5
通讯作者：
Kmiecik, Sebastian
中科院分区：
文献类型：
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作者：
Kurcinski, Mateusz;Kolinski, Andrzej;Kmiecik, Sebastian
磷酸化激酶诱导结构域（pKID）与其相互作用结构域（KIX）的复合物是研究内在未折叠蛋白质执行其功能的机制的模型系统。这些机制尚未完全理解。使用一个有效的粗粒度模型，从头计算模拟进行的耦合折叠和结合的pKID的KIX。模拟从未结合的、随机定位的和无序的pKID结构开始。在模拟过程中，pKID链及其位置保持完全不受限制，而KIX骨架仅限于接近天然的波动。从头计算模拟这种大规模的构象转变，不受任何知识的约束pKID结构，仍然无法进入经典模拟。我们的模拟恢复合奏的瞬态遇到复杂的实验结果吻合得很好。我们发现，一个关键的折叠和结合步骤是连接到一个预先形成的nativelike片段的pKID螺旋和KIX表面之间形成弱的本地相互作用。一旦该核形成，pKID链可以从很大程度上无序的遭遇系综浓缩成天然结合和有序的构象。所观察到的机制是让人想起一个成核冷凝模型，一个常见的情况下折叠的球状蛋白质。
A complex of the phosphorylated kinase-inducible domain (pKID) with its interacting domain (KIX) is a model system for studies of mechanisms by which intrinsically unfolded proteins perform their functions. These mechanisms are not fully understood. Using an efficient coarse-grained model, ab initio simulations were performed of the coupled folding and binding of the pKID to the KIX. The simulations start from an unbound, randomly positioned and disordered pKID structure. During the simulations the pKID chain and its position remain completely unrestricted, while the KIX backbone is limited to near-native fluctuations. Ab initio simulations of such large-scale conformational transitions, unaffected by any knowledge about the bound pKID structure, remain inaccessible to classical simulations. Our simulations recover an ensemble of transient encounter complexes in good agreement with experimental results. We find that a key folding and binding step is linked to the formation of weak native interactions between a preformed nativelike fragment of a pKID helix and KIX surface. Once that nucleus forms, the pKID chain may condense from a largely disordered encounter ensemble to a natively bound and ordered conformation. The observed mechanism is reminiscent of a nucleation condensation model, a common scenario for folding of globular proteins.