Yagi Kiyoshi, Ito Shingo, Sugita Yuji
Theoretical Molecular Science Laboratory, RIKEN Cluster for Pioneering Research, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Computational Biophysics Research Team, RIKEN Center for Computational Science, 7-1-26 minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
J Phys Chem B. 2021 May 13;125(18):4701-4713. doi: 10.1021/acs.jpcb.1c01862. Epub 2021 Apr 29.
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. 2007, 126, 164103) 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 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.
了解酶促反应的分子机制在生物化学和生物物理学中至关重要。在此，我们介绍了GENESIS程序中混合量子力学/分子力学（QM/MM）计算的新功能，以计算酶促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），将其作为GENESIS的共享库调用。其次，实现了搜索MEP的算法，将弦方法（E等人，2007年，126，164103）与缓冲MM区域的能量最小化相结合。GENESIS中实现的方法应用于一种酶，磷酸丙糖异构酶，它在四个质子转移过程中将磷酸二羟丙酮转化为3-磷酸甘油醛。QM/MM分子动力学模拟显示，使用密度泛函紧束缚（DFTB）时性能大于1 ns/天，使用混合密度泛函理论B3LYP-D3时性能为10 - 30 ps/天。这些性能使我们不仅能够使用QM/MM计算来计算MEP，还能计算酶促反应的平均力势（PMF）。在QM/MM计算中，使用B3LYP-D3获得的势垒高度为13 kcal/mol，与实验结果一致。PMF计算中构象采样的影响以及电子结构计算的水平（DFTB与B3LYP-D3）表明，无需高计算成本即可获得可靠的酶促反应计算协议。
