Predicting effects of "weak interactions" quantitatively using advanced simulation

• Project Area: Biophysical Chemistry for Material Symbiosis
• Project/Area Number: 21H05510
• Research Category: Grant-in-Aid for Transformative Research Areas (A)
• Allocation Type: Single-year Grants
• Review Section: Transformative Research Areas, Section (II)
• Research Institution: Tokyo Institute of Technology
• Principal Investigator: 北尾 彰朗 東京工業大学, 生命理工学院, 教授 (30252422)
• Project Period (FY): 2021-09-10 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000); Fiscal Year 2022: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2021: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
• Keywords: 複合体立体構造予測 / 結合親和性予測 / ColDock / evERdock / PaCS-MD/MSM

Outline of Research at the Start

本研究では、生体内で「弱い相互作用」によってタンパク質とナノマテリアルなどが形成する複合体立体構造や結合親和性を予測し、結合がもたらす効果を予測する先端的な分子シミュレーションを開発する。これをリガンドやナノマテリアルと細胞表面受容体などとの「弱い相互作用」の研究に応用することで、先端的な分子シミュレーション法をマテリアル・シンバイオシスに活用可能にし、相互作用の基礎的な知見を得ることを目指す。

Outline of Annual Research Achievements

前年度に引き続き、複合体立体構造から解離を行うdPaCS-MD/MSM法、解離状態から結合・解離サイクルを繰り返すa/dPaCS-MD/MSM法やColDock法、evERdock法をタンパク質とナノマテリアルの複合体などの立体構造予測にも利用できるようにシミュレーション法やモデルの開発・改良を行った。領域内の共同研究を中心として様々な分子複合体を対象に研究を展開した。具体的には、ヘルペスウイルスのglycoprotein BとPILRαの相互作用、物質共生に大きくかかわるPEG-抗PEG抗体の弱い相互作用、味覚受容体のアミノ酸認識、SGLT1による糖の選択的認識、アデノシン A2A 受容体と低分子化合物の相互作用などの研究を領域内の共同研究者の実験データと比較しながら研究を展開した。glycoprotein BとPILRαの複合体やSGLTと糖の相互作用に関しては、先行研究で指摘されていた分子力場依存性が我々の研究でも確認でき、これを踏まえた研究を行った。SGLT1に関しては、当初実験で適当な立体構造が見られなかったため、SGLT2の実験構造からホモロジーモデリングを行ったが、年度中に実験構造が得られたのでこれに基づく再計算を行った。PEG-抗PEG抗体の相互作用に関しては、九大森研究室との共同研究でTI抗原とTD抗原における違いを明らかにし、この結果を含む論文の執筆を進めている。味覚受容体のアミノ酸認識においては、2種類の類似したアミノ酸の結合の強さの違いをもたらす原因を明らかにすべく計算を行った。これらの場合はPaCS-MDを使わなくてもシミュレーション時間内でしばしば解離や再結合が見られたので、多数のMD計算を実行し更にMSM解析を行うことで、結合と解離の過程の詳しい解析を行うことができた。

Research Progress Status

令和4年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和4年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] National Tsing Hua University（台湾）(その他の国・地域)
• [Int'l Joint Research] University of Toronto(カナダ)
• [Int'l Joint Research] University of East Anglia(英国)
• [Journal Article] Engineering of an in-cell protein crystal for fastening a metastable conformation of a target miniprotein (2023)
  • Author(s): Mariko Kojima, Satoshi Abe, Tadaomi Furuta, Duy Phuoc Tran, Kunio Hirata, Keitaro Yamashita, Yuki Hishikawa, Akio Kitao, Takafumi Ueno
  • Journal Title: Biomaterial Science Volume: 11 Issue: 4 Pages: 1350-1357
  • DOI: 10.1039/d2bm01759h
  • Peer Reviewed
• [Journal Article] Structure of MotA, a flagellar stator protein, from hyperthermophile (2023)
  • Author(s): Tatsuro Nishikino, Norihiro Takekawa, Duy Phuoc Tran, Jun-ichi Kishikawa, Mika Hirose, Sakura Onoe, Seiji Kojima, Michio Homma, Akio Kitao, Takayuki Kato and Katsumi Imada
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 631 Pages: 78-85
  • DOI: 10.1016/j.bbrc.2022.09.072
  • Peer Reviewed
• [Journal Article] Dependence of Vibrational Energy Transfer on Distance in a Four-helix Bundle Protein: Equidistant Increments with the Periodicity of α Helices (2022)
  • Author(s): Satoshi Yamashita,Misao Mizuno, Kazuhiro Takemura, Akio Kitao, and Yasuhisa Mizutani
  • Journal Title: The Journal of Physical Chemistry B Volume: - Issue: 17 Pages: 3283-3290
  • DOI: 10.1021/acs.jpcb.2c00956
  • Peer Reviewed
• [Journal Article] Principal Component Analysis and Related Methods for Investigating the Dynamics of Biological Macromolecules (2022)
  • Author(s): Akio Kitao
  • Journal Title: J Multidisciplinary Scientific Journal Volume: 5 Issue: 2 Pages: 298-317
  • DOI: 10.3390/j5020021
  • Peer Reviewed / Open Access
• [Journal Article] Conserved GYXLI Motif of FlhA Is Involved in Dynamic Domain Motions of FlhA Required for Flagellar Protein Export (2022)
  • Author(s): Minamino Tohru、Kinoshita Miki、Inoue Yumi、Kitao Akio、Namba Keiichi
  • Journal Title: Microbiology Spectrum Volume: 10 Issue: 4
  • DOI: 10.1128/spectrum.01110-22
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of the hexamerization of SARS-CoV-2 endoribonuclease and modeling of RNA structures bound to the hexamer (2022)
  • Author(s): Tran Duy Phuoc、Taira Yuta、Ogawa Takumi、Misu Ryoga、Miyazawa Yoshiki、Kitao Akio
  • Journal Title: Scientific Reports Volume: 12 Issue: 1
  • DOI: 10.1038/s41598-022-07792-2
  • Peer Reviewed / Open Access
• [Journal Article] Dissociation Pathways of the p53 DNA Binding Domain from DNA and Critical Roles of Key Residues Elucidated by dPaCS-MD/MSM (2022)
  • Author(s): Sobeh Mohamed Marzouk、Kitao Akio
  • Journal Title: Journal of Chemical Information and Modeling Volume: 62 Issue: 5 Pages: 1294-1307
  • DOI: 10.1021/acs.jcim.1c01508
  • Peer Reviewed
• [Journal Article] Regulatory Switching by Concerted Motions on the Microsecond Time Scale of the Oxygen Sensor Protein FixL (2021)
  • Author(s): Yamawaki Takeo、Mizuno Misao、Ishikawa Haruto、Takemura Kazuhiro、Kitao Akio、Shiro Yoshitsugu、Mizutani Yasuhisa
  • Journal Title: The Journal of Physical Chemistry B Volume: 125 Issue: 25 Pages: 6847-6856
  • DOI: 10.1021/acs.jpcb.1c01885
  • Peer Reviewed
• [Journal Article] Using molecular dynamics simulations to prioritize and understand AI-generated cell penetrating peptides (2021)
  • Author(s): Tran Duy Phuoc、Tada Seiichi、Yumoto Akiko、Kitao Akio、Ito Yoshihiro、Uzawa Takanori、Tsuda Koji
  • Journal Title: Scientific Reports Volume: 11 Issue: 1
  • DOI: 10.1038/s41598-021-90245-z
  • Peer Reviewed / Open Access
• [Journal Article] The role of the half-turn in determining structures of Alzheimer’s Aβ wild-type and mutants (2021)
  • Author(s): Hayward Steven、Kitao Akio
  • Journal Title: Journal of Structural Biology Volume: 213 Issue: 4 Pages: 107792-107792
  • DOI: 10.1016/j.jsb.2021.107792
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Binding free energy of protein/ligand complexes calculated using dissociation Parallel Cascade Selection Molecular Dynamics and Markov state model (2021)
  • Author(s): Hata Hiroaki、Phuoc Tran Duy、Marzouk Sobeh Mohamed、Kitao Akio
  • Journal Title: Biophysics and Physicobiology Volume: 18 Issue: 0 Pages: 305-316
  • DOI: 10.2142/biophysico.bppb-v18.037
  • NAID: 130008132038
  • ISSN: 2189-4779
  • Peer Reviewed / Open Access
• [Presentation] Revealing the complex formation / deformation process of anti-tumor suppressor p53 protein complexes in functioning (2023)
  • Author(s): Duy Phuoc Tran, Akio Kitao
  • Organizer: APATCC-10(Asia Pacific Conference of Theoretical and Computational Chemistry
  • Int'l Joint Research
• [Presentation] LPリング中のロッドの回転シミュレーション Simulating the rod rotation in LP-ring (2023)
  • Author(s): 北尾彰朗
  • Organizer: 2022年度べん毛研究交流会
• [Presentation] イオン透過に関わるMotAとMotBの相対運動 The relative motions of MotA and MotB in flagellar stator toward ion permeation） (2023)
  • Author(s): Duy Phuoc Tran
  • Organizer: 2022年度べん毛研究交流会
• [Presentation] 柔らかな分子の複合体形成と解離 (2022)
  • Author(s): 北尾彰朗
  • Organizer: シンポジウム「柔らかな分子系研究の発展」
  • Invited
• [Presentation] Conformational Change and Dissociation/Association of Biological Macromolecules Investigated by Parallel Cascade Selection Molecular Dynamics and Markov State Model (2022)
  • Author(s): Akio Kitao
  • Organizer: ABA, APPA&TBS Joint Congress2022
  • Int'l Joint Research / Invited
• [Presentation] PaCS-MD/MSM法を用いたキナーゼ複合体の結合速度論解析 (2022)
  • Author(s): 竹村和浩, 北尾彰朗
  • Organizer: 第22回日本蛋白質科学会年会
• [Presentation] Substrate Unbinding Mechanism of Candida rugosa Lipase Explored by Parallel Cascade Selections Molecular Dynamics and Markov State Model (2022)
  • Author(s): Darin Flamandita, Akio Kitao
  • Organizer: 第22回日本蛋白質科学会年会
• [Presentation] How EGCG pertubates the interaction between MDM2 and N-terminal domain of p53 (2022)
  • Author(s): Duy Phuoc Tran, Akio Kitao
  • Organizer: 第22回日本蛋白質科学会年会
• [Presentation] Binding Kinetics of Kinase Complexes by PaCS-MD/MSM (2022)
  • Author(s): 竹村和浩, 北尾彰朗
  • Organizer: 第60回日本生物物理学会年会
• [Presentation] Protein conformational change, association and dissociation observed using Fugaku and massively parallel molecular dynamics simulations (2022)
  • Author(s): Akio Kitao
  • Organizer: 第60回日本生物物理学会年会
• [Presentation] 高速分子動画を補完する構造変化の自由エネルギー地形と経路・流量の解析 (2022)
  • Author(s): 北尾彰朗
  • Organizer: 令和４年度新学術領域研究「高速分子動画」シンポジウム
• [Presentation] 分子動力学計算におけるタンパク質の二面角遷移の解析 (2022)
  • Author(s): 吉岡美月, 北尾彰朗
  • Organizer: 第16回分子科学討論会
• [Presentation] 並列カスケード選択分子動力学法を用いた生体分子の解離課程解析 (2022)
  • Author(s): 中矢光, チャンフズイ, 北尾彰朗
  • Organizer: 第16回分子科学討論会
• [Presentation] Analysis of High Speed Atomic Force Microscopy Image of FlhAc（FlhAcの高速原子間力顕微鏡画像の解析） (2022)
  • Author(s): 大沢陸輝, 北尾彰朗
  • Organizer: 第60回日本生物物理学会年会
• [Presentation] The relative motion of MotA around MotB in bacterial flagellar stator (2022)
  • Author(s): Duy Phuoc Tran, Akio Kitao
  • Organizer: 第60回日本生物物理学会年会
• [Presentation] FlhAcの高速原子間力顕微鏡画像の解析 (2022)
  • Author(s): 大沢陸輝, 寺原直矢, 古寺哲幸, 今田勝巳, 南野徹, 北尾彰朗
  • Organizer: 第36回分子シミュレーション討論会
• [Presentation] How different glycopeptide affects the binding of glycoprotein B to paired immunoglobulin-like type 2 receptor (2022)
  • Author(s): Ting-Yi Chu, Duy Phuoc Tran, Akio Kitao
  • Organizer: 第36回分子シミュレーション討論会
• [Presentation] 線形応答理論を応用した効率的な分子動 力学シミュレーションに基づく自由エネル ギー解析 (2022)
  • Author(s): 生澤真司, 北尾彰朗
  • Organizer: 第36回分子シミュレーション討論会
• [Presentation] How partial agonist ligands induce the conformational changes of Adenosine A2a receptor (2022)
  • Author(s): Duy Phuoc Tran, Akio Kitao
  • Organizer: 第36回分子シミュレーション討論会
• [Presentation] Molecular Dynamics investigation of binding affinities between amino acid and taste receptor (2022)
  • Author(s): Thai-Hao Nguyen, Duy Phuoc Tran, Akio Kitao
  • Organizer: 第36回分子シミュレーション討論会
• [Presentation] The Effect of Tricaprylin-Water Interface on the Conformational Dynamics of Candida antarctica Lipase B (2022)
  • Author(s): Tegar Wijaya, Akio Kitao
  • Organizer: 第36回分子シミュレーション討論会
• [Presentation] SARS-CoV-2 エンドリボヌクレアーゼのオリゴマー化阻害 (2021)
  • Author(s): 北尾彰朗
  • Organizer: 新学術領域「高速分子動画」Web セミナー「構造生物学・化学・計算科学を融合させたウイルス・パンデミックに対する取り組み」
  • Invited
• [Presentation] インシリコシミュレーションで探るタンパク質複合体の結合親和性とキネティックス (2021)
  • Author(s): 北尾彰朗
  • Organizer: 日本薬学会構造活性相関部門構造活性フォーラム2021「次期スーパーコンピュータ「富岳」時代の計算創薬」
  • Invited
• [Presentation] Simulated dissociation/association dynamics between proteins and other molecules (2021)
  • Author(s): Akio Kitao
  • Organizer: TSRC WS「Protein Dynamics」
  • Int'l Joint Research / Invited
• [Presentation] Observing biomolecules through a lens of computer simulation (2021)
  • Author(s): 北尾彰朗, TRAN Phuoc Duy
  • Organizer: C2C Program Kick off symposium
  • Int'l Joint Research / Invited
• [Presentation] PaCS-MD/MSM to investigate protein motions and association/dissociation of protein complexes (2021)
  • Author(s): Akio Kitao
  • Organizer: Symposium on Computer Simulations and Cryo-ET/EM of Complex Biomolecular Systems
  • Int'l Joint Research / Invited
• [Presentation] Molecular movie of protein association/dissociation dynamics (2021)
  • Author(s): 北尾彰朗
  • Organizer: 第59回日本生物物理学会年会シンポジウム（原子レベルの動的構造解析が拓く生体分子機能の理解）
  • Invited
• [Presentation] Roles of hydration/dehydration for dissociation, association and stabilization of protein complexes (2021)
  • Author(s): Akio Kitao
  • Organizer: Pacific Chem 2021
  • Int'l Joint Research / Invited
• [Presentation] Transport mechanisms of ions, peptides and proteins through the biological membrane (2021)
  • Author(s): Akio Kitao
  • Organizer: Pacific Chem 2021
  • Int'l Joint Research / Invited
• [Presentation] Atomic mechanism of the complete association of intrinsically disordered peptide to protein (2021)
  • Author(s): Duy Tran, Akio Kitao
  • Organizer: XXXII IUPAP Conference on Computational Physics(ccp2021)
  • Int'l Joint Research
• [Presentation] 結合速度論解析 (2021)
  • Author(s): 北尾彰朗
  • Organizer: 「富岳」2021ワークショップ
  • Invited
• [Presentation] Application of ColDock to docking of cryptic pockets (2021)
  • Author(s): Ryunosuke Kiuchi, Kazuhiro Takemura, Akio Kitao
  • Organizer: 第59回日本生物物理学会年会
• [Presentation] DNA bending enhances the dissociation of tetrameric p53’s coredomains (2021)
  • Author(s): Duy Tran, Akio Kitao
  • Organizer: 第59回日本生物物理学会年会
• [Presentation] Unguided Binding MD of Protein-Protein Complexes by PPI-ColDock (2021)
  • Author(s): Kazuhiro Takemura, Akio Kitao
  • Organizer: 第59回日本生物物理学会年会
• [Presentation] Dynamics of Close-Open State of CALB Obtained by Parallel Cascade Molecular Dynamics Simulation and The Markov State Model (2021)
  • Author(s): Wijaya Tegar N., 北尾彰朗
  • Organizer: 第21回日本蛋白質科学会年会
• [Presentation] Investigating the dissociation process and kinetic rates of DBD-p53/DNA complex by PaCS-MD and MSM (2021)
  • Author(s): マルゾーク モハメド, 北尾彰朗
  • Organizer: 第21回日本蛋白質科学会年会
• [Presentation] Unguided Binding MD of Protein-Protein Complexes by PPI-ColDock (2021)
  • Author(s): 竹村和浩, 北尾彰朗
  • Organizer: 第21回日本蛋白質科学会年会
• [Presentation] Benchmarking the free energy calculation of PaCS-MD/MSM (2021)
  • Author(s): チャン フ ズイ, 畑 宏明,中矢 光, 北尾彰朗
  • Organizer: 第21回日本蛋白質科学会年会
• [Presentation] Predicting the complex conformations of protein/intrinsically disordered peptide complexes using a method termed a/dPaCS-MD (2021)
  • Author(s): Duy Phuoc Tran, Akio Kitao
  • Organizer: The Protein Society-35th Anniversary Symposium
  • Int'l Joint Research
• [Presentation] Binding free energy calculation with dPaCS-MD/MSM (2021)
  • Author(s): Duy Phuoc Tran, Akio Kitao
  • Organizer: C2C Program Kick off symposium
  • Int'l Joint Research
• [Book] Bacterial and Archaeal Motility, Chapter 3 Molecular Simulation to Investigate Open-Close Motion of a Flagellar Export Apparatus Protein FlhAC (2023)
  • Author(s): Akio Kitao
  • Total Pages: 402
  • Publisher: Springer
  • ISBN: 9781071630600
• [Book] PLASMA MEMBRANE SHAPING, Section 5 Chapter 27 Molecular dynamics (2022)
  • Author(s): Kazuhiro Takemura, Akio Kitao
  • Total Pages: 451
  • Publisher: Academic Press
  • ISBN: 9780323899116
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