Challenge in computational science toward the identification of the reaction pathway for the formation of nucleic acids-small molecule complexes

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K22254
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 37:Biomolecular chemistry and related fields
• Research Institution: Osaka University
• Principal Investigator: Nakatani Kazuhiko 大阪大学, 産業科学研究所, 教授 (70237303)
• Project Period (FY): 2019-06-28 – 2022-03-31
• Keywords: RNA / 標的 / 低分子 / 創薬 / 誘導適合 / 量子計算

Outline of Final Research Achievements

The present study aimed to understand the essential nature of induced conformational small molecule-RNA binding with dynamic conformational changes. For the structurally analyzed small molecule DANP-C bulge complex, we generated an initial structure in which the DANP on the opposite side of the cytosine bulge was pulled apart at an appropriate distance perpendicular to the hydrogen bond, and the stable structure from that structure was determined by simulation. As a result, it was found that there are multiple transition states before the complex structure is formed, i.e., the coordinates at which the original structure is no longer restored, and a clue to the structure of the transition states was obtained through precise structural analysis. Parameters for quantum chemical calculations were derived, and structural optimization at the wb97xd/6-31+gd level of the density functional theory was performed in water.

Free Research Field

生物化学

Academic Significance and Societal Importance of the Research Achievements

これから将来極めて有望であり、必ずや創薬研究に必要となるRNAを標的とする低分子創成のボトルネックは、RNA－低分子複合体形成が誘導適合型であるためシミュレーションが難しいことにある。この問題点を解決し、我が国がRNAを標的とする低分子創成研究で主導権を握ることを目的として、最新の革新的計算科学手法を世界にさきがけて低分子－核酸複合体という巨大分子系に適用し、低分子－RNA複合体形成経路の計算科学による解明を基盤とするRNA標的低分子創成の加速、本領域における主導権の掌握を狙った。結果的には目標に到達できなかったが、本研究は、RNA標的低分子創薬に資する研究である。