Accurate QM/MM Free Energy Calculations of Enzyme Reactions: Methylation by Catechol O-Methyltransferase.
Accurate QM/MM Free Energy Calculations of Enzyme Reactions: Methylation by Catechol O-Methyltransferase.
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DOI：
10.1021/ct0501102
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发表时间：
2005-08
影响因子：
5.5
通讯作者：
T. Rod;U. Ryde
中科院分区：
文献类型：
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作者：
T. Rod;U. Ryde
我们最近描述了一种计算精确量子力学自由能的方法[Rod， t.h.；Ryde， U.物理学。[j].农业工程学报，2003,19(4):481 - 481。我们称之为量子力学热力学循环摄动（QTCP）的方法，采用分子力学力场对相空间进行采样，然后使用热力学循环来估计QM/MM自由能的变化。在这里，我们详细讨论了方法，并测试了一种基于不同热力学循环的方法。我们还证明了一种处理氢连接原子的新方法使自由能变化收敛得更快，并且可以进行更高精度的外推。最后在QTCP方法的框架下讨论了量子力学自由能（QM/MM-FE）方法。所有考虑的方法都适用于由儿茶酚o -甲基转移酶催化的儿茶酚酸的甲基化。我们通过计算沿预定反应路径在固定QM区域之间的步长自由能变化来计算反应的自由能垒。利用QTCP方法，在B3LYP官能团和6-311++G（2d,2p）基集水平上，得到了正向反应的活化自由能为69 kJ/mol，逆向反应的活化自由能为90 kJ/mol。正反应的数值与75 kJ/mol的实验值非常吻合。基于QM/MM- fe方法的结果与这些值相差小于10 kJ/mol，表明QM/MM- fe方法可能是计算QM/MM自由能变化的一种相当准确和廉价的替代方法。此外，还将结果与固定分子力学环境下获得的势垒以及在真空中优化的结构进行了比较。所有计算得到的自由能势垒都很好地收敛。当前QTCP方法实现中的一个主要近似是QM区域是固定的。这种近似导致了良好收敛的自由能势垒，这在类似的研究中一直是一个问题。
We recently described a method to compute accurate quantum mechanical free energies [Rod, T. H.; Ryde, U. Phys. Rev. Lett. 2005, 94, 138302]. The method, which we term quantum mechanical thermodynamic cycle perturbation (QTCP), employs a molecular mechanics force field to sample phase space and, subsequently, a thermodynamic cycle to estimate QM/MM free energy changes. Here, we discuss the methodology in detail and test an approach based on a different thermodynamic cycle. We also show that a new way of treating hydrogen link atoms makes the free energy changes converge faster and that extrapolation to higher accuracy can be performed. We finally discuss the quantum mechanical free energy (QM/MM-FE) method in the framework of the QTCP method. All methods considered are applied to the methylation of catecholate catalyzed by catechol O-methyltransferase. We compute the free energy barrier for the reaction by computing free energy changes in steps between fixed QM regions along a predetermined reaction pathway. Using the QTCP approach, an extrapolated activation free energy of 69 kJ/mol for the forward reaction and 90 kJ/mol for the reverse reaction are obtained at the level of the B3LYP functional and the 6-311++G(2d,2p) basis set. The value for the forward reaction is in excellent agreement with the experimental value of 75 kJ/mol. Results based on the QM/MM-FE method differ by less than 10 kJ/mol from those values, indicating that QM/MM-FE may be a fairly accurate and cheap alternative to calculate QM/MM free energy changes. Moreover, the results are compared to barriers obtained with a fixed molecular mechanics environment as well as with structures optimized in a vacuum. All the computed free energy barriers are well converged. A major approximation in the current implementation of the QTCP method is that the QM region is fixed. The approximation leads to well-converged free energy barriers, which has been a problem in similar studies.