Olsson Mats H M, Siegbahn Per E M, Warshel Arieh
Chemistry Department, University of Southern California, Los Angeles, California 90089-1062, USA.
J Am Chem Soc. 2004 Mar 10;126(9):2820-8. doi: 10.1021/ja037233l.
Elucidating the role of nuclear quantum mechanical (NQM) effects in enzyme catalysis is a topic of significant current interest. Despite the great experimental progress in this field it is important to have theoretical approaches capable of evaluating and analyzing nuclear quantum mechanical contributions to catalysis. In this study, we use the catalytic reaction of lipoxygenase, which is characterized by an extremely large kinetic isotope effect, as a challenging test case for our simulation approach. This is done by applying the quantum classical path (QCP) method with an empirical valence bond potential energy surface. Our computational strategy evaluates the relevant NQM corrections and reproduces the large observed kinetic isotope effect and the temperature dependence of the H atom transfer reaction while being less successful with the D atom transfer reaction. However, the main point of our study is not so much to explore the temperature dependence of the isotope effect but rather to develop and validate an approach for calculations of nuclear quantum mechanical contributions to activation free energies. Here, we find that the deviation between the calculated and observed activation free energies is small for both H and D at all investigated temperatures. The present study also explores the nature of the reorganization energy in the enzyme and solution reactions. It is found that the outer-sphere reorganization energy is extremely small. This reflects the fact that the considered reaction involves a very small charge transfer. The implication of this finding is discussed in the framework of the qualitative vibronic model. The main point of the present study is, however, that the rigorous QCP approach provides a reliable computational tool for evaluating NQM contributions to catalysis even when the given reaction includes large tunneling contributions. Interestingly, our results indicate that the NQM effects in the lipoxygenase reaction are similar in the enzyme and in the reference solution reactions, and thus do not contribute to catalysis. We also reached similar conclusions in studies of other enzymes.
阐明核量子力学（NQM）效应在酶催化中的作用是当前一个备受关注的重要课题。尽管该领域在实验方面取得了巨大进展，但拥有能够评估和分析核量子力学对催化作用贡献的理论方法仍然很重要。在本研究中，我们将脂氧合酶的催化反应作为我们模拟方法的一个具有挑战性的测试案例，该反应具有极大的动力学同位素效应。这是通过应用具有经验价键势能面的量子经典路径（QCP）方法来实现的。我们的计算策略评估了相关的NQM修正，并重现了观察到的大动力学同位素效应以及H原子转移反应的温度依赖性，而对于D原子转移反应则不太成功。然而，我们研究的主要目的并非探索同位素效应的温度依赖性，而是开发和验证一种计算核量子力学对活化自由能贡献的方法。在这里，我们发现在所有研究温度下，H和D的计算活化自由能与观察到的活化自由能之间的偏差都很小。本研究还探讨了酶和溶液反应中重组能的性质。发现外层重组能极小。这反映了所考虑的反应涉及非常小的电荷转移这一事实。在定性振动电子模型的框架内讨论了这一发现的含义。然而，本研究的主要观点是，即使给定反应包含大的隧穿贡献，严格的QCP方法也为评估NQM对催化的贡献提供了可靠的计算工具。有趣的是，我们的结果表明，脂氧合酶反应中的NQM效应在酶和参考溶液反应中相似，因此对催化没有贡献。我们在其他酶的研究中也得出了类似的结论。
