Multi-scale simulation of protein-ligand binding process

• Project/Area Number: 24570179
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biophysics
• Research Institution: The University of Tokyo
• Principal Investigator: TERADA Tohru 東京大学, 農学生命科学研究科, 准教授 (40359641)
• Research Collaborator: NEGAMI Tatsuki
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 分子動力学シミュレーション / タンパク質 / リガンド / パスウェイ / マルチコピー・マルチスケール法 / 粗視化モデル / 自由エネルギー計算 / MARTINI / マルチスケールシミュレーション

Outline of Final Research Achievements

I established a method to reproduce the protein-ligand binding process in a coarse-grained molecular dynamics (MD) simulations. This method was applied to many protein-ligand pairs that differ in terms of the shape of the ligand-binding pocket and the physicochemical properties of the pocket and the ligand. The comparison of the results suggested that the ligands enter the ligand-binding pockets through specific pathways. Furthermore, I also established a method to refine the ligand-binding pathway with all-atom MD simulations and to calculate free-energy profile along the pathway.

Research Products

• [Journal Article] Coarse-Grained Molecular Dynamics Simulations of Protein-Ligand Binding (2014)
  • Author(s): Tatsuki Negami, Kentaro Shimizu, Tohru Terada
  • Journal Title: Journal of Computational Chemistry Volume: Volume 35 Issue: 25 Pages: 1835-1845
  • DOI: 10.1002/jcc.23693
  • Peer Reviewed / Open Access
• [Presentation] Protein-ligand binding processes studied by coarse-grained molecular dynamics simulations (2014)
  • Author(s): Tohru Terada, Tatsuki Negami, Kentaro Shimizu
  • Organizer: 日本生物物理学会第52回年会
  • Place of Presentation: 札幌コンベンションセンター（北海道）
  • Year and Date: 2014-09-25 – 2014-09-27
  • Invited
• [Presentation] The factors determining protein-ligand binding processes revealed by comparative coarse-grained simulations (2014)
  • Author(s): Tatsuki Negami, Tohru Terada, Kentaro Shimizu
  • Organizer: 日本生物物理学会第52回年会
  • Place of Presentation: 札幌コンベンションセンター（北海道）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Protein-Ligand Binding Simulation with the Martini Coarse-Grained Force Field (2014)
  • Author(s): Tatsuki Negami, Kentaro Shimizu, Tohru Terada
  • Organizer: Biophysical Society 58th Annual Meeting
  • Place of Presentation: Moscone Center, San Francisco, California, USA
• [Presentation] Comparative simulations of protein-ligand binding processes using the MARTINI coarse-grained force field (2013)
  • Author(s): Tatsuki Negami, Tohru Terada, Kentaro Shimizu
  • Organizer: 日本生物物理学会第51回年会
  • Place of Presentation: 国立京都国際会館, 京都市
• [Presentation] Coarse-grained MD simulations of ligand binding to proteins: Effect of the conformational changes of the proteins (2012)
  • Author(s): Tatsuki Negami, Tohru Terada, Kentaro Shimizu
  • Organizer: 日本生物物理学会第50回年会
  • Place of Presentation: 名古屋大学（愛知県）