Molecular Insights into the Intrinsic Dynamics and Their Roles During Catalysis in Pin1 Peptidyl-prolyl Isomerase
Molecular Insights into the Intrinsic Dynamics and Their Roles During Catalysis in Pin1 Peptidyl-prolyl Isomerase
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Pin1 肽基脯氨酰异构酶催化过程中内在动力学及其作用的分子洞察
DOI：
10.1021/acs.jpcb.2c02095
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Saito Shinji
中科院分区：
文献类型：
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作者：
Mori Toshifumi;Saito Shinji
蛋白质本质上是动态的，并且在很宽的时间尺度上改变构象。虽然构象动力学已经被认识到对蛋白质功能是重要的，例如，在活性-稳定性权衡中，它们在酶催化过程中如何发挥作用已经争论了几十年。通过研究Pin 1肽基脯氨酰异构酶使用广泛的分子动力学模拟，在这里，我们讨论了如何缓慢的内在动力学的Pin 1观察到的NMR弛豫分散实验发生和耦合到异构化反应的分子细节。特别地，我们分析了骨架N-H键的角相关函数，发现在apo态中，在310螺旋附近发生了缓慢的构象转变。螺旋区的这些事件进一步影响配体结合位点附近的残基。该螺旋的展开导致螺旋区域和配体结合环之间的紧密氢键，从而形成稳定的卷曲结构。螺旋和卷曲的结构被认为是特征的Pin 1-配体配合物与配体在反式和顺式状态，分别。这些结果表明，在缓慢的动力学Pin 1的异构化反应的变化发生通过移位的螺旋和卷曲状态，其中的平衡是依赖于配体异构化状态的人口。
Proteins are intrinsically dynamic and change conformations over a wide range of time scales. While the conformational dynamics have been realized to be important for protein functions, e.g., in activity–stability trade-offs, how they play a role during enzyme catalysis has been of debate over decades. By studying Pin1 peptidyl-prolyl isomerase using extensive molecular dynamics simulations, here we discuss how the slow intrinsic dynamics of Pin1 observed in the NMR relaxation dispersion experiment occur and couple to isomerization reactions in molecular detail. In particular, we analyze the angular correlation functions of the backbone N–H bonds and find that slow conformational transitions occur at about the 310helix in the apo state. These events at the helical region further affect the residues at about the ligand binding site. Unfolding of this helix leads to a tight hydrogen bond between the helical region and the ligand binding loop, thus forming a stable coiled structure. The helical and coiled structures are found to be characteristic of the Pin1–ligand complex with the ligand in the trans and cis states, respectively. These results indicate that the changes in the slow dynamics of Pin1 by the isomerization reaction occur via the shift in populations of the helical and coiled states, where the balance is dependent on the ligand isomerization states.