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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Simulating disorder-order transitions in molecular recognition of unstructured proteins: Where folding meets binding.
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Simulating disorder-order transitions in molecular recognition of unstructured proteins: Where folding meets binding.

机译：模拟无结构蛋白质分子识别中的无序转换：折叠遇到结合。

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摘要

A microscopic study of functional disorder-order folding transitions coupled to binding is performed for the p27 protein, which derives a kinetic advantage from the intrinsically disordered unbound form on binding with the phosphorylated cyclin A-cyclin-dependent kinase 2 (Cdk2) complex. Hierarchy of structural loss during p27 coupled unfolding and unbinding is simulated by using high-temperature Monte Carlo simulations initiated from the crystal structure of the tertiary complex. Subsequent determination of the transition-state ensemble and the proposed atomic picture of the folding mechanism coupled to binding provide a microscopic rationale that reconciles the initiation recruitment of p27 at the cyclin A docking site with the kinetic benefit for a disordered alpha-helix in the unbound form of p27. The emerging structural polarization in the ensemble of unfoldingunbinding trajectories and in the computationally determined transition-state ensemble is not determined by the intrinsic folding preferences of p27 but rather is attributed to the topological requirements of the native intermolecular interface to order beta-hairpin and beta-strand of p27 that could be critical for nucleating rapid folding transition coupled to binding. In agreement with the experimental data, the disorder-order folding transition for p27 is largely determined by the functional requirement to form a specific intermolecular interface that ultimately dictates the folding mechanism and overwhelms any local folding preferences for creating a stable alpha-helix in the p27 structure before overcoming the major free energy barrier.
机译：对p27蛋白进行了与结合相关的功能紊乱顺序折叠过渡的显微镜研究，该过程从与磷酸化细胞周期蛋白A-细胞周期蛋白依赖性激酶2（Cdk2）结合时固有的无序结合形式获得了动力学优势。通过使用由三元复合物的晶体结构引发的高温蒙特卡洛模拟，模拟了p27偶联的解折叠和解结合过程中结构损失的层次。随后确定过渡态集合和结合结合的折叠机制的原子图，提供了微观原理，使p27在细胞周期蛋白A停靠位点的起始募集与未结合的无序α螺旋的动力学益处相协调。 p27的形式。在解开解束轨迹的集合中和在计算确定的过渡态集合中出现的结构极化不是由p27的固有折叠偏好决定的，而是归因于天然分子间界面对β-发夹和β- p27链对成核至与结合结合的快速折叠过渡至关重要。与实验数据一致，p27的无序折叠折叠主要由功能要求决定，以形成特定的分子间界面，最终决定折叠机制并压倒了在p27中创建稳定的α-螺旋的任何局部折叠偏好克服主要的自由能源壁垒之前的结构。

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