Bayesian optimization for goal-oriented multi-objective inverse material design.

Bayesian optimization (BO) can accelerate material design requiring time-consuming experiments. However, although most material designs require tuning of multiple properties, the efficiency of multi-objective (MO) BO in time-consuming experimental material design remains unclear, due to the complexity of handling multiple objectives. This study introduces MO BO method that efficiently achieves predefined goals and shows that by focusing on achieving the goals, BO can efficiently accelerate realistic MO design problems with small efforts. Benchmarks showed that the proposed BO method dramatically reduced the number of experiments needed to achieve goals relative to a baseline method. Virtual MO inverse design experiments with realistic material design problems were also performed, during which the proposed method could achieve goals within only around ten experiments in average and showed over 1000-fold acceleration relative to the random sampling for the most difficult case. The introduction of goal-oriented BO will precede real-world application of BO.

Deep Neural Networks for Multicomponent Molecular Systems.

Deep neural networks (DNNs) represent promising approaches to molecular machine learning (ML). However, their applicability remains limited to single-component materials and a general DNN model capable of handling various multicomponent molecular systems with composition data is still elusive, while current ML approaches for multicomponent molecular systems are still molecular descriptor-based. Here, a general DNN architecture extending existing molecular DNN models to multicomponent systems called MEIA is proposed. Case studies showed that the MEIA architecture could extend two exiting molecular DNN models to multicomponent systems with the same procedure, and that the obtained models that could learn both the molecular structure and composition information with equal or better accuracies compared to a well-used molecular descriptor-based model in the best model for each case study. Furthermore, the case studies also showed that, for ML tasks where the molecular structure information plays a minor role, the performance improvements by DNN models were small; while for ML tasks where the molecular structure information plays a major role, the performance improvements by DNN models were large, and DNN models showed notable predictive accuracies for an extremely sparse dataset, which cannot be modeled without the molecular structure information. The enhanced predictive ability of DNN models for sparse datasets of multicomponent systems will extend the applicability of ML in the multicomponent material design. Furthermore, the general capability of MEIA to extend DNN models to multicomponent systems will provide new opportunities to utilize the progress of actively developed single-component DNNs for the modeling of multicomponent systems.

Molecular Mechanism of the Reaction Specificity in Threonine Synthase: Importance of the Substrate Conformations.

Threonine synthase (ThrS) catalyzes the final chemical reaction of l-threonine biosynthesis from its precursor, O-phospho-l-homoserine. As the phosphate ion generated in its former half reaction assists its latter reaction, ThrS is recognized as one of the best examples of product-assisted catalysis. In our previous QM/MM study, the chemical reactions for the latter half reactions, which are critical for the product-assisted catalysis, were revealed. However, accurate free energy changes caused by the conformational ensembles and entrance of water molecules into the active site are unknown. In the present study, by performing long-time scale MD simulations, the free energy changes by the divalent anions (phosphate or sulfate ions) and conformational states of the intermediate states were theoretically investigated. We found that the calculated free energy double differences are in good agreement with the experimental results. We also revealed that the phosphate ion contributes to forming hydrogen bonds that are suitable for the main reaction progress. This means that the conformation of the active site amino acid residues and the substrate, and hence, the tunable catalysis, are controlled by the product phosphate ion, and this clearly demonstrates a molecular mechanism of the product-assisted catalysis in ThrS.

Molecular mechanisms of substrate specificities of uridinecytidine kinase.

A uridine-cytidine kinase (UCK) catalyzes the phosphorylation of uridine (Urd) and cytidine (Cyd) and plays a significant role in the pyrimidine-nucleotide salvage pathway. Unlike ordinary ones, UCK from Thermus thermophilus HB8 (ttCK) loses catalytic activity on Urd due to lack of a substrate binding ability and possesses an unusual amino acid, i.e. tyrosine 93 (Tyr93) at the binding site, whereas histidine (His) is located in the other UCKs. Mutagenesis experiments revealed that a replacement of Tyr93 by His or glutamine (Gln) recovered catalytic activity on Urd. However, the detailed molecular mechanism of the substrate specificity has remained unclear. In the present study, we performed molecular dynamics simulations on the wild-type ttCK, two mutant ttCKs, and a human UCK bound to Cyd and three protonation forms of Urd to elucidate their substrate specificity. We found three residues, Tyr88, Tyr/His/Gln93 and Arg152 in ttCKs, are important for recognizing the substrates. Arg152 contributes to induce a closed form of the binding site to retain the substrate, and the N3 atom of Urd needed to be deprotonated. Although Tyr88 tightly bound Cyd, it did not sufficiently bind Urd because of lack of the hydrogen bonding. His/Gln93 complemented the interaction of Tyr88 and raised the affinity of ttCK to Urd. The crucial distinction between Tyr and His or Gln was a role in the hydrogen-bonding network. Therefore, the ability to form both hydrogen-bonding donor and accepter is required to bind both Urd and Cyd.

A QM/MM study of the L-threonine formation reaction of threonine synthase: implications into the mechanism of the reaction specificity.

Threonine synthase catalyzes the most complex reaction among the pyridoxal-5'-phosphate (PLP)-dependent enzymes. The important step is the addition of a water molecule to the Cß-Cα double bond of the PLP-α-aminocrotonate aldimine intermediate. Transaldimination of this intermediate with Lys61 as a side reaction to form α-ketobutyrate competes with the normal addition reaction. We previously found that the phosphate ion released from the O-phospho-l-homoserine substrate plays a critical role in specifically promoting the normal reaction. In order to elucidate the detailed mechanism of this "product-assisted catalysis", we performed comparative QM/MM calculations with an exhaustive search for the lowest-energy-barrier reaction pathways starting from PLP-α-aminocrotonate aldimine intermediate. Satisfactory agreements with the experiment were obtained for the free energy profile and the UV/vis spectra when the PLP pyridine N1 was unprotonated and the phosphate ion was monoprotonated. Contrary to an earlier proposal, the base that abstracts a proton from the attacking water was the ε-amino group of Lys61 rather than the phosphate ion. Nevertheless, the phosphate ion is important for stabilizing the transition state of the normal transaldimination to form l-threonine by making a hydrogen bond with the hydroxy group of the l-threonine moiety. The absence of this interaction may account for the higher energy barrier of the side reaction, and explains the mechanism of the reaction specificity afforded by the phosphate ion product. Additionally, a new mechanism, in which a proton temporarily resides at the phenolate O3' of PLP, was proposed for the transaldimination process, a prerequisite step for the catalysis of all the PLP enzymes.

Substrate-mediated proton relay mechanism for the religation reaction in topoisomerase II.

The DNA religation reaction of yeast type II topoisomerase (topo II) was investigated to elucidate its metal-dependent general acid/base catalysis. Quantum mechanical/molecular mechanical calculations were performed for the topo II religation reaction, and the proton transfer pathway was examined. We found a substrate-mediated proton transfer of the topo II religation reaction, which involves the 3' OH nucleophile, the reactive phosphate, water, Arg781, and Tyr782. Metal A stabilizes the transition states, which is consistent with a two-metal mechanism in topo II. This pathway may be required for the cleavage/religation reaction of topo IA and II and will provide a general explanation for the catalytic mechanism in the topo IA and II.