Transition Path Sampling Based Calculations of Free Energies for Enzymatic Reactions: The Case of Human Methionine Adenosyl Transferase and Plasmodium vivax Adenosine Deaminase.
Transition Path Sampling Based Calculations of Free Energies for Enzymatic Reactions: The Case of Human Methionine Adenosyl Transferase and Plasmodium vivax Adenosine Deaminase.
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DOI：
10.1021/acs.jpcb.2c03251
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发表时间：
2022-07-28
影响因子：
3.3
通讯作者：
Schwartz, Steven D.
中科院分区：
文献类型：
--
作者：
Balasubramani, Sree Ganesh;Schwartz, Steven D.
过渡路径取样（TPS）被广泛用于计算凝聚相体系的反应速率、过渡态结构和反应坐标。在这里，我们讨论了使用TPS反应轨迹系综结合酶催化反应的基于窗口的采样技术来计算自由能的方案。我们计算的自由能曲线的人甲硫氨酸S-腺苷转移酶（MAT 2A）酶和间日疟原虫腺苷脱氨酶（pvADA）酶催化的反应，以评估这种方法的准确性。MAT 2A催化S-腺苷-L-甲硫氨酸的形成遵循SN 2机制，并且使用我们的方法，我们估计该反应的自由能垒为16 kcal mol−1，这与实验测量的活化能17.27 kcal mol−1非常一致。此外，对于pvADA酶催化的反应，我们估计自由能势垒为21 kcal mol−1，计算的自由能分布与实验观察预测的相似。通过在TPS中采用我们的简单方法计算自由能提供了比伞形采样等方法显著的优势，因为它不受任何施加的外部偏差的影响，与实验测量相比是准确的，并且具有合理的计算成本。
Transition path sampling (TPS) is widely used for the calculations of reaction rates, transition state structures, and reaction coordinates of condensed phase systems. Here we discuss a scheme for the calculation of free energies using the ensemble of TPS reactive trajectories in combination with a window-based sampling technique for enzyme-catalyzed reactions. We calculate the free energy profiles of the reactions catalyzed by the human methionine S-adenosyltransferase (MAT2A) enzyme and the Plasmodium vivax adenosine deaminase (pvADA) enzyme to assess the accuracy of this method. MAT2A catalyzes the formation of S-adenosine-l-methionine following a SN2 mechanism, and using our method, we estimate the free energy barrier for this reaction to be 16 kcal mol−1, which is in excellent agreement with the experimentally measured activation energy of 17.27 kcal mol−1. Furthermore, for the pvADA enzyme-catalyzed reaction we estimate a free energy barrier of 21 kcal mol−1, and the calculated free energy profile is similar to that predicted from experimental observations. Calculating free energies by employing our simple method within TPS provides significant advantages over methods such as umbrella sampling because it is free from any applied external bias, is accurate compared to experimental measurements, and has a reasonable computational cost.
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影响因子：
4.4
作者：
BEUTLER, TC;VANGUNSTEREN, WF
通讯作者：
VANGUNSTEREN, WF
DOI：
10.1073/pnas.0901522106
发表时间：
2009-06-16
影响因子：
11.1
作者：
Bloom, Jesse D.;Arnold, Frances H.
通讯作者：
Arnold, Frances H.
影响因子：
3
作者：
BROOKS, BR;BRUCCOLERI, RE;KARPLUS, M
通讯作者：
KARPLUS, M
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML
影响因子：
5.5
作者：
Hub, Jochen S.;de Groot, Bert L.;van der Spoel, David
通讯作者：
van der Spoel, David