Exploring the Minimum-Energy Pathways and Free-Energy Profiles of Enzymatic Reactions with QM/MM Calculations
Exploring the Minimum-Energy Pathways and Free-Energy Profiles of Enzymatic Reactions with QM/MM Calculations
复制标题
DOI：
10.1021/acs.jpcb.1c01862
复制
发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
K. Yagi;S. Ito;Y. Sugita
中科院分区：
文献类型：
--
作者：
K. Yagi;S. Ito;Y. Sugita
了解酶反应的分子机制在生物化学和生物物理学中具有重要意义。这里，我们在Genesis程序中引入了混合量子力学/分子力学(QM/MM)计算的新功能，以计算酶反应的最小能量路径(MEP)和自由能分布。为此，在Genesis中开发了一个接口，以利用高度并行的电子结构程序QSimulate-QM(https://qsimulate.com)，将其称为来自Genesis的共享库。其次，结合字符串方法(E等人)，实现了搜索MEP的算法。J·化学。物理2007、126、16410317477585)，其中缓冲MM区域的能量最小化。在Genesis中实施的方法被应用于磷酸丙糖异构酶，该酶在四个质子转移过程中将磷酸二羟基丙酮转化为3-磷酸甘油醛。QM/MM-分子动力学模拟表明，密度泛函紧束缚(DFTB)和混合密度泛函理论(B3LYP-D3)的性能分别大于1 ns/d和10-30ps/d。这些性能使我们不仅可以计算MEP，还可以使用QM/MM计算酶反应的平均作用力势(PMF)。在QM/MM计算中，用B3LYP-D3方法计算得到的势垒高度为13kcal~(-1)，与实验结果相吻合。PMF计算中构象采样的影响和电子结构计算的水平(DFTB与B3LYP-D3)为酶反应提供了可靠的计算方案，而不需要很高的计算成本。
Understanding molecular mechanisms of enzymatic reactions is of vital importance in biochemistry and biophysics. Here, we introduce new functions of hybrid quantum mechanical/molecular mechanical (QM/MM) calculations in the GENESIS program to compute the minimum-energy pathways (MEPs) and free-energy profiles of enzymatic reactions. For this purpose, an interface in GENESIS is developed to utilize a highly parallel electronic structure program, QSimulate-QM (https://qsimulate.com), calling it as a shared library from GENESIS. Second, algorithms to search the MEP are implemented, combining the string method (E et al. J. Chem. Phys.2007, 126, 16410317477585 ) with the energy minimization of the buffer MM region. The method implemented in GENESIS is applied to an enzyme, triosephosphate isomerase, which converts dihyroxyacetone phosphate to glyceraldehyde 3-phosphate in four proton-transfer processes. QM/MM-molecular dynamics simulations show performances of greater than 1 ns/day with the density functional tight binding (DFTB), and 10–30 ps/day with the hybrid density functional theory, B3LYP-D3. These performances allow us to compute not only MEP but also the potential of mean force (PMF) of the enzymatic reactions using the QM/MM calculations. The barrier height obtained as 13 kcal mol–1 with B3LYP-D3 in the QM/MM calculation is in agreement with the experimental results. The impact of conformational sampling in PMF calculations and the level of electronic structure calculations (DFTB vs B3LYP-D3) suggests reliable computational protocols for enzymatic reactions without high computational costs.