www.asiachem.news December 2021 | 61 higher; Fig. 3(e) did exhibit this fact. In other words, Fig. 3(d) suggests that the amorphous carbon sandwiched between two CNTs can transform into the sp2-bond-rich structure by annealing even at relatively low temperatures below 2000K. This prediction was verified experimentally, leading to the discovery of new carbon material with high thermoelectric properties.21 In the QM/MM method,the reaction center is treated by the accurate and high-cost QM calculation and the rest by the low-cost MM calculation. Lactate Dehydrogenase The hybrid quantum mechanics/molecular mechanics (QM/MM) and microiteration methods are often used together to optimize the structure of macromolecules like enzymes. In the QM/MM method,22-24 the reaction center is treated by the accurate and high-cost QM calculation and the rest by the low-cost MM calculation. In the case of enzymatic reactions, the QM calculation is often used for regions involving chemical bond rearrangements, while the MM calculation is used for the surrounding proteins. The microiteration method is a technique to reduce the number of QM calculations in geometry optimization using the QM/MM method, where the coordinates of the MM atoms are optimized as the coordinates of the QM atoms change.25,26 In general, the geometry optimization using the MM calculation is less expensive than a single QM calculation. Thus, the total calculation time can be significantly reduced compared to the geometry optimization when all atoms are treated equivalently. In the microiteration method, the position of the MM atom changes according to the structural change of the QM part. Therefore, it is not applicable to the case where the structural change of the MM part promotes the reaction. To solve this problem, the multistructural microiteration (MSM) method was proposed, in which the entire molecule is represented by a single QM structure and a weighted sum of multiple MM structures, as schematically illustrated in Fig. 4(a).27 The weight of each MM structure is determined by a Boltzmann distribution and varies according to the QM structure. Recently, by combining the MSM and AFIR methods, a reaction path was calculated in which L-lactate dehydrogenase (LDH) in rabbit muscle catalyzes the transformation of pyruvate to L-lactate. Fig 4(b) illustrates an experimentally proposed mechanism,28 where (1) the open LDH binds the substrate, (2) the LDH changes from the open form to the closed one, (3) the chemical transformation of pyruvate to L-lactate occurs in the closed LDH, (4) the LDH changes from the closed form to the open one, and (5) the product is released from the open LDH. Before the calculations, we performed replica exchange molecular dynamics simulations and prepared six open-form and six closedform structures. The MSM method was used to represent the MM structure as a weighted sum of these six open and six closed structures. The QM/MM-ONIOM method was used as the QM/MM method. The QM part was calculated at the B3LYP/6-31+G(d,p) level, and the MM part was calculated using the AMBER force field. Fig. 4(c) shows the obtained energy profile. Among the three peaks, the middle peak corresponds to the TS for the pyruvate to L-lactate chemical transformation. At this TS, the closed-form structure was dominant as shown in Fig. 4(d), which is consistent with the mechanism in Fig. 4(b). Moreover, the transition from the open-form to the closedform structure occurred around the first peak, and the transition from the closed-form to the open-form structure occurred around the third peak. These are again consistent with the mechanism in Fig. 4(b). Because the first and third peaks describe changes in the surrounding protein structure, these peaks are Figure 4(a) Schematic illustration of the MSM method, (b) experimentally proposed reaction mechanism of LDH, (c) energy profile along the minimum energy path for the pyruvate to L-lactate chemical transformation obtained by combining the AFIR and MSM methods, (d) variation of the weights of the MM structures along the path in (c). termed as surrounding structural TS (SSTS) in Fig. 4(c). The combination of the MSM and AFIR methods could be a powerful computational tool for elucidating the mechanism of enzyme reactions. Difluoroglycine Synthesis Finally, we introduce an attempt to propose a new synthetic method by the AFIR method. To achieve this, we adopt a new concept called Quantum Chemistry-aided Retrosynthetic Analysis (QCaRA), which systematically explores decomposition and isomerization paths of a target molecule using automated reaction path search methods like the AFIR method and proposes a synthetic method for the target molecule as a reverse reaction of the obtained path. QCaRA requires the backward search of the reaction path from the product to the reactant; hence, searching for the path through the high barrier must be considered as well. This is because a pathway that proceeds with a low barrier from the reactant may have a high barrier when traced from the product to the reactant. The AFIR method can be used as a reaction path search engine in QCaRA since its capability of exhaustive search, including high barrier paths, has been proved.15 QCaRA was proposed in 2013,9 and the results of its hypothetical application to search for the formation path of glycine molecule was presented. However, over the next seven years, QCaRA was not used in actual organic synthesis. In 2020,19 the first successful discovery of organic reaction by QCaRA was reported in the development
RkJQdWJsaXNoZXIy NDU2MA==