Theoretical analysis of biohydrogenomics

• Project Area: HYDROGENOMICS: Creation of Innovative Materials, Devices, and Reaction Processes using Higher-Order Hydrogen Functions
• Project/Area Number: 19H05047
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Science and Engineering
• Research Institution: University of Tsukuba
• Principal Investigator: 重田 育照 筑波大学, 計算科学研究センター, 教授 (80376483)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 電子状態計算 / 反応解析 / 構造解析 / プロトン移動反応 / 電子移動経路 / 酸解離定数 / プロトン化状態 / 酸化還元電位 / NiFeヒロドゲナーゼ / 生体ハイドロジェノミクス / 第一原理計算 / 分子動力学計算 / プロトン移動経路 / ヒドロゲナーゼ / 分子軌道法 / 分子動力学法 / 同位体効果

Outline of Research at the Start

ヒドロゲナーゼは水素酸化とプロトン還元を可逆的に触媒する酵素であり、その反応メカニズムの学術的な興味もさることながら、水素分子の貯蔵・生産を可能にするバイオエネルギー源としても大変魅力的な研究対象である。実験で多くのことが解明されているものの、その詳細に関しては未知の部分も多く残されており、理論研究により相補的な情報を提供することが本研究の役割である。

Outline of Annual Research Achievements

ヒドロゲナーゼは遷移金属を含む活性部位（触媒サイト）において水素分子をプロトンと電子へと可逆的に変換する役割を果たす酵素であり、ある種の嫌気的生物はその電子エネルギーを利用し生命システムを維持してきた。この機能は言わば生体内燃料電池であり、ヒドロゲナーゼの機能を理解することは、ハイドロジェノミクスの分野を生物系へ拡張する上で極めて本質的である。
本研究では、完全酸化状態である[NiFe]ヒドロゲナーゼの分子状水素による再活性化機構を明らかにするため、嫌気性条件下で得られた新たなX線、および中性子線結晶構造解析結果の構造の妥当性、およびその安定性を検証することを目的としている。また、水素分子との反応についての知見を得ることで、再活性化の可能性を検討した。
従来、再活性化が遅いNi-Aとして同定されていた構造は酸素により過剰に酸化された構造であったが、今回得られた構造は反応サイクル中のそれと類似しており、QM/MM計算による網羅計算により、NiとFe間を架橋する酸素種はO2-、Niの価数は+3、スピンは低スピン状態であることが同定された。また、再活性化が速いNi-BについてはNiとFe間を架橋する酸素種はOH-、Niの価数は+3、スピンは低スピン状態であることが同定された。本研究により、新規構造の妥当性を検証するとともに、結晶構造解析からは観測が困難な水素の空間配置の決定、および遷移金属の価電子数とスピン状態が明らかとなった。
R02年度は特に、完全酸化された構造からの水素による再活性化過程について、QM/MM計算を行なった。酸化状態では、活性サイトに水素分子の吸着が直接起こらないことを確認した。したがって、分子状の水素ではなく原子状、あるいは自ら生ずるオキソニウムイオン、ヒドロニウムイオン、あるいは電子移動が起こる必要があることを意味している。

Research Progress Status

令和2年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和2年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] Chulalongkorn University(タイ)
• [Int'l Joint Research] Max Planck Institute(ドイツ)
• [Journal Article] Molecular Motions of Imidazole in Poly(vinylphosphonic acid)-Imidazole Composites Investigated by Molecular Dynamics Simulations (2021)
  • Author(s): Hori Yuta、Suetake Toshiya、Shigeta Yasuteru、Ida Tomonori、Mizuno Motohiro
  • Journal Title: Chemistry Letters Volume: 50 Issue: 1 Pages: 17-20
  • DOI: 10.1246/cl.200635
  • NAID: 130007965988
  • Peer Reviewed
• [Journal Article] The Folding of Trp-cage is Regulated by Stochastic Flip of the Side Chain of Tryptophan (2021)
  • Author(s): Yasuda Takunori、Shigeta Yasuteru、Harada Ryuhei
  • Journal Title: Chemistry Letters Volume: 50 Issue: 1 Pages: 162-165
  • DOI: 10.1246/cl.200699
  • NAID: 130007965969
  • Peer Reviewed
• [Journal Article] Why are lopinavir and ritonavir effective against the newly emerged Coronavirus 2019?: Atomistic insights into the inhibitory mechanisms (2020)
  • Author(s): B. Nutho, P. Mahalapbutr, K. Hengphasatporn, N.C. Pattaranggoon, N. Simanon, Y. Shigeta, S. Hannongbua, T. Rungrotmongkol
  • Journal Title: Biochemistry Volume: 59 Issue: 18 Pages: 1769-1779
  • DOI: 10.1021/acs.biochem.0c00160
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Neutron crystallography of copper amine oxidase reveals keto/enolate interconversion of the quinone cofactor and unusual proton sharing (2020)
  • Author(s): Takeshi Murakawa, Kazuo Kurihara, Mitsuo Shoji, Chie Shibazaki, Tomoko Sunami, Taro Tamada, Naomine Yano, Taro Yamada, Katsuhiro Kusaka, Mamoru Suzuki, Yasuteru Shigeta, Ryota Kuroki, Hideyuki Hayashi, Takato Yano, Katsuyuki Tanizawa, Motoyasu Adachi, Toshihide Okajima
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 印刷中 Issue: 20 Pages: 10818-10824
  • DOI: 10.1073/pnas.1922538117
  • Peer Reviewed / Open Access
• [Journal Article] Regenerations of Initial Velocities in Parallel Cascade Selection Molecular Dynamics (PaCS-MD) Enhance the Conformational Transitions of Proteins (2020)
  • Author(s): Aida Hayato、Shigeta Yasuteru、Harada Ryuhei
  • Journal Title: Chemistry Letters Volume: 49 Issue: 7 Pages: 798-801
  • DOI: 10.1246/cl.200196
  • NAID: 130007872518
  • Peer Reviewed
• [Journal Article] The Dynamics of S-adenosyl-methionine and S-adenosyl-homocysteine in Mouse Dnmt1 is Driven by Their Structural Flexibilities (2020)
  • Author(s): Yasuda Takunori、Shigeta Yasuteru、Harada Ryuhei
  • Journal Title: Chemistry Letters Volume: 49 Issue: 7 Pages: 785-788
  • DOI: 10.1246/cl.200223
  • NAID: 130007872573
  • Peer Reviewed
• [Journal Article] Understanding the Detection Mechanisms and Ability of Molecular Hydrogen on ThreeDimensional Bicontinuous Nanoporous Reduced Graphene Oxide (2020)
  • Author(s): Yoshikazu Ito, Megumi Kayanuma, Yasuteru Shigeta, Jun-ichi Fujita, Yoichi Tanabe
  • Journal Title: Materials Volume: 13 Issue: 10 Pages: 2259-2259
  • DOI: 10.3390/ma13102259
  • NAID: 120007166901
  • Peer Reviewed / Open Access
• [Journal Article] Analytical Method Using a Scaled Hypersphere Search for High-Dimensional Metadynamics Simulations (2020)
  • Author(s): Mitsuta Yuki、Shigeta Yasuteru
  • Journal Title: Journal of Chemical Theory and Computation Volume: 16 Issue: 6 Pages: 3869-3878
  • DOI: 10.1021/acs.jctc.0c00010
  • Peer Reviewed
• [Journal Article] Reaction Mechanism of Monomeric Sarcosine Oxidase with N-Cyclopropylglycine (2020)
  • Author(s): M.Shoji, Y.Abe, M.Boero, Y.Shigeta, Y.Nishiya
  • Journal Title: Physical Chemistry Chemical Physics Volume: - Issue: 29 Pages: 16552-16561
  • DOI: 10.1039/d0cp01679a
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Efficient Conformational Sampling of Collective Motions of Proteins with Principal Component Analysis-Based Parallel Cascade Selection Molecular Dynamics (2020)
  • Author(s): Yasuda Takunori、Shigeta Yasuteru、Harada Ryuhei
  • Journal Title: Journal of Chemical Information and Modeling Volume: 60 Issue: 8 Pages: 4021-4029
  • DOI: 10.1021/acs.jcim.0c00580
  • Peer Reviewed
• [Journal Article] Self-Associating Curved π-Electronic Systems with Electron-Donating and Hydrogen-Bonding Properties (2020)
  • Author(s): Haketa Yohei、Miyasue Mika、Kobayashi Yoichi、Sato Ryuma、Shigeta Yasuteru、Yasuda Nobuhiro、Tamai Naoto、Maeda Hiromitsu
  • Journal Title: Journal of the American Chemical Society Volume: 142 Issue: 38 Pages: 16420-16428
  • DOI: 10.1021/jacs.0c07751
  • Peer Reviewed
• [Journal Article] Tunneling matrix element and tunneling pathways of protein electron transfer calculated with a fragment molecular orbital method (2020)
  • Author(s): Kitoh-Nishioka Hirotaka、Shigeta Yasuteru、Ando Koji
  • Journal Title: The Journal of Chemical Physics Volume: 153 Issue: 10 Pages: 104104-104104
  • DOI: 10.1063/5.0018423
  • Peer Reviewed
• [Journal Article] Proton Conduction Mechanism in Proton-Conducting PVPA-<i>x</i>Im Composites Investigated by Theoretical Approaches (2020)
  • Author(s): HORI Yuta、SUETAKE Toshiya、IDA Tomonori、MIZUNO Motohiro、SHIGETA Yasuteru
  • Journal Title: Journal of Computer Chemistry, Japan Volume: 19 Issue: 4 Pages: 131-132
  • DOI: 10.2477/jccj.2020-0028
  • NAID: 130008009669
  • ISSN: 1347-1767, 1347-3824
  • Peer Reviewed
• [Journal Article] Membrane Permeability from Solvation Free Energy Calculation of Cyclic Dipeptide (CDP) (2020)
  • Author(s): YANAGI Kohki、HARADA Ryuhei、MITSUTA Yuki、SHIGETA Yasuteru
  • Journal Title: Journal of Computer Chemistry, Japan Volume: 19 Issue: 4 Pages: 125-127
  • DOI: 10.2477/jccj.2021-0008
  • NAID: 130008009673
  • ISSN: 1347-1767, 1347-3824
• [Journal Article] Reaction of threonine synthase with the substrate analogue 2-amino-5-phosphonopentanoate: Implications into the proton transfer at the active site (2020)
  • Author(s): Y. Machida, T. Murakawa, A. Sakai, M. Shoji, Y. Shigeta, H. Hayashi
  • Journal Title: Biochemistry Volume: 167 Issue: 4 Pages: 357-364
  • DOI: 10.1093/jb/mvz100
  • NAID: 40022210984
  • Peer Reviewed / Open Access
• [Journal Article] Multiple Virtual Screening Strategies for the Discovery of Novel Compounds Active Against Dengue Virus: A Hit Identification Study (2020)
  • Author(s): K. Hengphasatporn, A. Garon, P. Wolschann, T. Langer, Y. Shigeta, T. Nguyen Thanh Huynh, W. Chavasiri, T. Saelee, S. Boonyasuppayakorn, T. Rungrotmongkol
  • Journal Title: Scientia Pharmaceutica Volume: 88 Issue: 1 Pages: 2-2
  • DOI: 10.3390/scipharm88010002
  • NAID: 120007132939
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Estimation of Acid Dissociation Constants (pKa) of N-Containing Heterocycles in DMSO and Transferability of Gibbs Free Energy in Different Solvent Conditions (2020)
  • Author(s): Hengphasatporn Kowit、Matsui Toru、Shigeta Yasuteru
  • Journal Title: Chemistry Letters Volume: 49 Issue: 3 Pages: 307-310
  • DOI: 10.1246/cl.190946
  • NAID: 130007805919
  • Peer Reviewed
• [Journal Article] Distribution of Conter Ions in Negatively-charged Lipid/Water/Air Interface: Molecular Dynamics Study (2020)
  • Author(s): T. Takahashi, R. Harada, Y. Shigeta
  • Journal Title: Chemistry Letters Volume: 49 Issue: 4 Pages: 361-363
  • DOI: 10.1246/cl.200043
  • NAID: 130007828859
  • Peer Reviewed
• [Journal Article] Local Structures and Dynamics of Imidazole Molecules in Poly(vinylphosphonic acid)?Imidazole Composite Investigated by Molecular Dynamics (2020)
  • Author(s): Hori Yuta、Suetake Toshiya、Shiota Yoshihito、Yoshizawa Kazunari、Shigeta Yasuteru、Ida Tomonori、Mizuno Motohiro
  • Journal Title: ACS Applied Polymer Materials Volume: 2 Issue: 4 Pages: 1561-1568
  • DOI: 10.1021/acsapm.9b01222
  • Peer Reviewed
• [Journal Article] Elucidation of the entire Kok cycle for photosynthetic water oxidation by the large-scale quantum mechanics/molecular mechanics calculations: Comparison with the experimental results by the recent serial femtosecond crystallography (2019)
  • Author(s): Shoji Mitsuo、Isobe Hiroshi、Shen Jian-Ren、Suga Michihiro、Akita Fusamichi、Miyagawa Koichi、Shigeta Yasuteru、Yamaguchi Kizashi
  • Journal Title: Chemical Physics Letters Volume: 730 Pages: 416-425
  • DOI: 10.1016/j.cplett.2019.06.026
  • Peer Reviewed
• [Journal Article] Accessing the Accuracy of Density Functional Theory through Structure and Dynamics of the Water/Air Interface (2019)
  • Author(s): Ohto Tatsuhiko、Dodia Mayank、Xu Jianhang、Imoto Sho、Tang Fujie、Zysk Frederik、Kuehne Thomas D.、Shigeta Yasuteru、Bonn Mischa、Wu Xifan、Nagata Yuki
  • Journal Title: The Journal of Physical Chemistry Letters Volume: 10 Issue: 17 Pages: 4914-4919
  • DOI: 10.1021/acs.jpclett.9b01983
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Covid-19関連タンパク質に対する統合的インシリコリポジショニング (2021)
  • Author(s): 重田育照
  • Organizer: HPCIオープンセミナー「スーパーコンピュータとCOVID-19」
  • Invited
• [Presentation] 計算化学による生命機能の解析:医薬分野との協働に向けて (2020)
  • Author(s): 重田育照
  • Organizer: 第93回 日本生化学会大会
  • Invited
• [Presentation] Covid-19関連タンパク質に対する統合的インシリコリポジショニング (2020)
  • Author(s): 重田育照
  • Organizer: 第9回 JCAHPC セミナー（第4回OFP 利用活用報告会）「人類と地球を守るスーパーコンピューティング」
  • Invited
• [Presentation] Computational Studies on Octanol/water Partition Coefficient of Organic Molecules (2020)
  • Author(s): Y. Shigeta
  • Organizer: 7th International Conference on Chemical and Biological Sciences
  • Int'l Joint Research / Invited
• [Presentation] Theoretical Investigation on Photofunctional pi-electron Materials (2019)
  • Author(s): Y. Shigeta
  • Organizer: pi-system figuration European-Japanese workshop 201
  • Int'l Joint Research / Invited
• [Presentation] Theoretical Studies on Membrane Permeability of Middle-sized Molecular Drugs using Implicit Membrane Models (2019)
  • Author(s): Y. Shigeta
  • Organizer: 5th Japan-Thai workshop on Theoretical and Computational Chemistry 2019
  • Int'l Joint Research / Invited
• [Presentation] Theoretical Studies on Membrane Permeability of Middle-sized Molecular Drugs (2019)
  • Author(s): Y. Shigeta
  • Organizer: 10th The Asian Consortium on Computational Materials Science
  • Int'l Joint Research / Invited
• [Presentation] Theoretical Studies on Reaction Mechanisms of Metalloenzymes: QM/MM analyses (2019)
  • Author(s): Y. Shigeta
  • Organizer: 23rd International Annual Symposium on Computational Science and Engineering
  • Int'l Joint Research / Invited
• [Presentation] データ同化型分子動力学計算法の開発 (2019)
  • Author(s): 重田育照
  • Organizer: 膜タンパク質研究会2019
  • Invited
• [Presentation] 青色受容タンパク質クリプトクロムの多様な機能と磁気感受応答に関する理論的アプローチ (2019)
  • Author(s): 重田育照
  • Organizer: 量子生命科学会第１回大会
  • Invited