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This work was partly supported by the JSPS Grants-in-Aid for Scientific Research (JP20H05453, JP20H05088, JP21H05419, and JP22H04916), MEXT Grants-in-Aid for Scientific Research on Innovative Areas (JP21H05419), JST PRESTO grant number JPMJPR19G6, and a research grant from The Mazda Foundation. Some computations were performed using computer facilities at the Research Institute for Information Technology, Kyushu University; the Research Center for Computational Science, Okazaki, Japan (Project:22-IMS-C122); and the Multidisciplinary Cooperative Research Program in CCS, University of Tsukuba. M.B. thanks the HPC Center at the University of Strasbourg funded by the Equipex Equip@Meso project, the CPER Alsacalcul/Big Data, and the Grand Equipement National de Calcul Intensif (GENCI) under allocation DARI-A0120906092 and A0140906092. We acknowledge Editage (www.editage.com) for English language editing.

Janus kinases (JAKs) are nonreceptor protein tyrosine kinases that play a role in a broad range of cell signaling. JAK2 and JAK3 have been involved in the pathogenesis of common lymphoid-derived diseases and leukemia cancer. Thus, inhibition of both JAK2 and JAK3 can be a potent strategy to reduce the risk of these diseases. In the present study, the pharmacophore models built based on the commercial drug tofacitinib and the JAK2/3 proteins derived from molecular dynamics (MD) trajectories were employed to search for a dual potent JAK2/3 inhibitor by a pharmacophore-based virtual screening of 54 synthesized pyrazolone derivatives from an in-house data set. Twelve selected compounds from the virtual screening procedure were then tested for their inhibitory potency against both JAKs in the kinase assay. The

The structural stabilities of the monoclinic and tetragonal phases of Si-doped HfO$_{2}$ at finite temperatures were analyzed using a computational scheme to assess the effects of impurity doping. The finite temperature effects considered in this work represented lattice vibration and impurity configuration effects. The results show that 6% Si doping stabilizes the tetragonal phase at room temperature, although a higher concentration of Si is required to stabilize the tetragonal phase at zero temperature. These data indicate that lattice vibration and impurity configuration effects are important factors determining structural stability at finite temperatures., Comment: 5 pages, 3 figures

Hsp104 and its bacterial homolog ClpB form hexameric ring structures and mediate protein disaggregation. The disaggregated polypeptide is thought to thread through the central channel of the ring. However, the dynamic behavior of Hsp104 during disaggregation remains unclear. Here, we reported the stochastic conformational dynamics and a split conformation of Hsp104 disaggregase from Chaetomium thermophilum (CtHsp104) in the presence of ADP by X-ray crystallography, cryo-electron microscopy (EM), and high-speed atomic force microscopy (AFM). ADP-bound CtHsp104 assembles into a 65 left-handed spiral filament in the crystal structure at a resolution of 2.7 Å. The unit of the filament is a hexamer of the split spiral structure. In the cryo-EM images, staggered and split hexameric rings were observed. Further, high-speed AFM observations showed that a substrate addition enhanced the conformational change and increased the split structure's frequency. Our data suggest that split conformation is an off-pathway state of CtHsp104 during disaggregation.

Recent advances in neutron crystallographic studies have provided structural bases for quantum behaviors of protons observed in enzymatic reactions. Thus, we resolved the neutron crystal structure of a bacterial copper amine oxidase, which contains a prosthetic copper ion and a protein-derived redox cofactor, topa quinone. We solved hitherto unknown structures of the active site, including a keto/enolate equilibrium of the cofactor with a non-planar quinone ring, unusual proton sharing between the cofactor and the catalytic base, and metal-induced deprotonation of a histidine residue that coordinates to the copper. Our findings show a refined active-site structure that gives detailed information on the protonation state of dissociable groups, such as the quinone cofactor, which are critical for catalytic reactions.

We report density functional calculations that clarify atom-scale mechanisms of vapor-phase epitaxial growth of GaN with gas sources of trimethylgallium and ammonia. We identify various stable adsorption structures of a Ga atom and NHx molecules (x = 0–3) on GaN(0001) surfaces and find that NH2 and NH units spontaneously intervene in Ga–Ga surface bonds on Ga-rich GaN(0001) surface. We then explore the reaction in which NH3 on the surface is decomposed and becomes an N-incorporated structure, −Ga–(NH)–Ga–, on the Ga-rich GaN(0001) and find that the reaction occurs with the energy barrier of 0.63 eV. Further exploration reveals that a reaction of H2 desorption occurs with the energy barrier of 2 eV, leaving the N atom incorporated in the Ga–N network. This barrier can be overcome when we consider the chemical potential of an H2 molecule in the gas phase at the growth temperature. This N incorporation on GaN is a new growth mechanism catalyzed by the growing surface., ファイル公開：2019-11-01

Photosystems are natural energy conversion systems evolved for over 2,700 million years. Among the photosystems, photosystem II (PSII) catalyzes the light-driven water decomposition reaction with the production of O2, protons and electrons to reduce plastoquinone. The reaction is important not only for understanding natural photosynthesis but also for creating efficient artificial photosynthesis. In this review, PSII catalytic intermediate states and their reaction mechanisms elucidated by experimental and theoretical approaches are introduced mainly following the development of the X-ray crystallography. For the O2 formation mechanism, two representative mechanisms, acid-base and radical coupling, are explained. Finally, we discuss the geometrical and electronic structures of inorganic model complex in comparison with those of the native catalytic center in PSII.

Non-equilibrium molecular dynamics simulations for the 2- and 3-phase systems were performed to investigate the flow with two free surfaces in a nanoscale, where solute, water, and argon were assigned as each phase. We observed that the behaviors of some 3-phase systems significantly differ from those of 2-phase systems. In all 2- phase systems, the solutes just diffused into the water phase. On the other hand, the solutes were transferred along the liquid-gas interfaces in the case of 3-phase systems with a large surface tension gradient. These results indicated that solutal Marangoni convection existed even in the nano-scale and it affected mass transfer greatly.

Dengue infection is caused by a mosquito-borne virus, particularly in children, which may even cause death. No effective prevention or therapeutic agents to cure this disease are available up to now. The dengue viral envelope (E) protein was discovered to be a promising target for inhibition in several steps of viral infection. Structure-based virtual screening has become an important technique to identify first hits in a drug screening process, as it is possible to reduce the number of compounds to be assayed, allowing to save resources. In the present study, pharmacophore models were generated using the common hits approach (CHA), starting from trajectories obtained from molecular dynamics (MD) simulations of the E protein complexed with the active inhibitor, flavanone (FN5Y). Subsequently, compounds presented in various drug databases were screened using the LigandScout 4.2 program. The obtained hits were analyzed in more detail by molecular docking, followed by extensive MD simulations of the complexes. The highest-ranked compound from this procedure was then synthesized and tested on its inhibitory efficiency by experimental assays.