How does Pin1 catalyze the cis-trans prolyl peptide bond isomerization? A QM/MM and mean reaction force study.
How does Pin1 catalyze the cis-trans prolyl peptide bond isomerization? A QM/MM and mean reaction force study.
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Pin1如何催化顺反脯氨酰肽键异构化？
DOI：
10.1021/jp307946h
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
A. Toro‐Labbé
中科院分区：
文献类型：
--
作者：
E. Vöhringer;F. Duarte;A. Toro‐Labbé
Pin 1代表特异性催化磷酸化苏氨酸或丝氨酸残基与脯氨酸之间的肽键异构化的酶。尽管它在许多与癌症和阿尔茨海默病相关的生物过程中作为分子计时器的相关性，但仍然缺少对催化作用的因素的详细了解。在这项研究中，我们采用广泛的QM/MM分子动力学模拟结合平均反应力（MRF），以辨别酶对反应机理和催化起源的影响。作为最近引入的方法，MRF将到达过渡态的活化自由能势垒分离为结构和电子贡献，提供了对酶功能的更详细描述。作为参考，我们首先研究了溶液中顺式异构化反应，得到了一个自由能垒和一个反应自由能，与前人的研究和实验结果一致。用新的平均反应力方法，在肽分子内的氢键被确定，稳定过渡态和减少电子的贡献的自由能垒。为了阐明Pin 1的催化机理，比较了Pin 1在溶液中和在酶催化腔中的反应。两者都产生相同的自由能垒的异构化的顺式形式，但不同的分解结构和电子的贡献的平均反应力。酶降低了结构重排达到过渡态所需的能量，这表明反应物不稳定，但通过特定的酶-肽氢键增加了对势垒的电子贡献。在反式异构化的逆反应中，酶大大改变了反应的能量学和机理。在异构化过程中，催化腔中不利的酶-肽相互作用改变了反应坐标，导致过渡态的能量差很小的两个最小值。这些小的自由能垒原则上应该使反应在室温下可行，一旦构象结合在正确的构象。
Pin1 represents an enzyme that specifically catalyzes the isomerization of peptide bonds between phosphorylated threonine or serine residues and proline. Despite its relevance as molecular timer in a number of biological processes related to cancer and Alzheimer disease, a detailed understanding of the factors contributing to the catalysis is still missing. In this study, we employ extensive QM/MM molecular dynamics simulations in combination with the mean reaction force (MRF) to discern the influence of the enzyme on the reaction mechanism and the origin of the catalysis. As a recently introduced method, the MRF separates the activation free energy barrier to reach the transition state into structural and electronic contributions providing a more detailed description of the enzyme's function. As a reference, we first study the isomerization starting from the cis form in solution and obtain a free energy barrier and a reaction free energy, which are in agreement with previous studies and experiment. With the new mean reaction force method, intramolecular hydrogen bonds in the peptide were identified that stabilize the transition state and reduce the electronic contribution to the free energy barrier. To elucidate the mechanism of catalysis of Pin1, the reaction in solution and in the catalytic cavity of the enzyme were compared. Both yield the same free energy barrier for the isomerization of the cis form, but with different decomposition in structural and electronic contributions by the mean reaction force. The enzyme reduces the energy required for structural rearrangements to reach the transition state, pointing to a destabilization of the reactant, but increases the electronic contribution to the barrier through specific enzyme-peptide hydrogen bonds. In the reverse reaction, the isomerization of the trans form, the enzyme alters the energetics and the mechanism of the reaction considerably. Unfavorable enzyme-peptide interactions in the catalytic cavity during the isomerization change the reaction coordinate, resulting in two minima with small energy differences to the transition state. These small free energy barriers should in principle make the reaction feasible at room temperature once the conformer is bound in the right conformation.
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