Scientific Computing Research Unit and Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
Institute of Infectious Disease and Molecular Medicine, Faculty of Health Science, University of Cape Town, Rondebosch 7701, South Africa.
Acc Chem Res. 2021 Nov 16;54(22):4120-4130. doi: 10.1021/acs.accounts.1c00477. Epub 2021 Nov 2.
Enzyme reactions are complex to simulate accurately, and none more so than glycoenzymes (glycosyltransferase and glycosidases). A rigorous sampling of the protein frame and the conformationally plural carbohydrate substrate coupled with an unbiased treatment of the electron dynamics is needed to discover the true reaction landscapes. Here, we demonstrate the effectiveness of two computational methods ported in libraries that we have developed. The first is a flat histogram free energy method called FEARCF capable of multidimensional sampling and rapidly converging to a complete coverage of phase space. The second, the Quantum Supercharger Library (QSL), is a method that accelerates the computation of the ab initio electronic wave function as well as the integral derivatives on graphical processing units (GPUs). These QSL accelerated computations form the core components needed for direct quantum dynamics and QM/MM dynamics when coupled with legacy codes such as GAMESS and NWCHEM, making state of the art hyper-parallel electronic computations in chemistry and chemical biology possible. The combination of QSL (acceleration of ab initio QM computation) and FEARCF (multidimensional hyper-parallel reaction dynamics) makes the simulation of ab initio QM/MM reaction dynamics of enzyme catalysis feasible. Enzymes that process carbohydrates pose an added challenge as their pyranose ring substrates span multidimensional conformational space whose sampling is an intimate function of the catalytic mechanism. Here, we use the pairing of FEARCF and QSL to simulate the catalytic effect of the glycoenzyme β--acetylglucosamine transferase (OGT). The reaction mechanism is discovered from a variable three bond reaction surface using SCCDFTB. The role of the OGT in distorting the pyranose ring of β--acetylglucosamine (GlcNAc) away from the equilibrium C chair conformation toward the E envelope needed for the transition state is discovered from its pucker free energy hypersurfaces (or free energy volume, FEV). A complete GlcNAc ring pucker HF 6-31g FEV is constructed from ab initio QM dynamics in vacuum and ab initio QM/MM dynamics in the OGT catalytic domain. The OGT is shown to clearly lower the pathway toward the transition state E ring conformer as well as stabilize it by 1.63 kcal/mol. Illustrated here is the use of QSL accelerated ab initio QM/MM dynamics that thoroughly explores carbohydrate catalyzed reactions through a FEARCF multidimensional sampling of the interdependence between reaction and conformational space. This demonstrates how experimentally inaccessible molecular and electronic mechanisms that underpin enzyme catalysis can be discovered by directly modeling the dynamics of these complex reactions.
酶反应的精确模拟很复杂，糖基酶（糖基转移酶和糖苷酶）则更为复杂。需要对蛋白质框架和构象多样的碳水化合物底物进行严格采样，并对电子动力学进行无偏处理，才能发现真正的反应景观。在这里，我们展示了我们开发的两个库中移植的两种计算方法的有效性。第一种是称为 FEARCF 的无平坦直方图自由能方法，能够进行多维采样，并迅速收敛到完整的相空间覆盖范围。第二种是量子超级充电器库 (QSL)，是一种加速从头算电子波函数计算以及图形处理单元 (GPU) 上积分导数计算的方法。这些 QSL 加速计算形成了与传统代码（如 GAMESS 和 NWCHEM）结合使用时进行直接量子动力学和 QM/MM 动力学所需的核心组件，使化学和化学生物学领域的最先进的超并行电子计算成为可能。QSL（从头算 QM 计算的加速）和 FEARCF（多维超并行反应动力学）的结合使得模拟酶催化的从头算 QM/MM 反应动力学成为可能。处理碳水化合物的酶带来了额外的挑战，因为它们的吡喃糖环底物跨越多维构象空间，其采样是催化机制的内在功能。在这里，我们使用 FEARCF 和 QSL 的组合来模拟糖基酶 β--乙酰氨基葡萄糖转移酶 (OGT) 的催化作用。使用 SCCDFTB 从可变三键反应表面发现反应机制。OGT 在将吡喃糖环 β--乙酰氨基葡萄糖（GlcNAc）从平衡 C 椅构象扭曲到过渡态所需的 E 信封中的作用是从其构象自由能超曲面（或自由能体积，FEV）中发现的。完整的 GlcNAc 环构象 HF 6-31g FEV 是从真空中的从头算 QM 动力学和 OGT 催化结构域中的从头算 QM/MM 动力学中构建的。结果表明，OGT 明显降低了通向过渡态 E 环构象的途径，并通过 1.63 kcal/mol 稳定了它。这里说明了如何使用 QSL 加速的从头算 QM/MM 动力学通过 FEARCF 对反应和构象空间之间的相互依赖性进行多维采样，彻底探索碳水化合物催化反应。这表明如何通过直接模拟这些复杂反应的动力学来发现支持酶催化的实验上无法获得的分子和电子机制。
