| Project/Area Number |
20K15737
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 43020:Structural biochemistry-related
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| Research Institution | Institute of Physical and Chemical Research |
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Principal Investigator |
Dokainish Hisham 国立研究開発法人理化学研究所, 開拓研究本部, 特別研究員 (20825575)
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| Project Period (FY) |
2020-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | IDR / Protein dynamics / enhanced sampling / Catalysis / MD simaulation / Enhanced Sampling / Chrosimate Mutase / Enzyme catalysis / Enhance sampling |
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| Outline of Research at the Start |
Enzymes, due to their role in catalysis, have long been considered to have a distinct folded conformation. Recent studies identified numerous enzymes with an intrinsically disordered region (IDR). To date, the effect of IDR on the structure of enzymes active sites as well as the energetics of the reaction path has not been studied. In this proposal, the effect of IDR on enzymatic reactions will be investigated using various computational chemistry methods.
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| Outline of Final Research Achievements |
The role of intrinsically disordered region (IDR) in enzymatic reactions was elucidated, using multiscale computational approach. This includes classical and enhanced sampling molecular dynamics (MD) simulations and Quantum mechanical (QM) calculations. MD results show that IDR induces large fluctuation in an engineered Chrosimate Mutase active site, allowing for a necessary substrate reorganization to form reactive complex. QM calculations confirmed the role of IDR in lowering the reaction barrier. The results shed the light on an unrecognized role of structural disorder in enzymatic reactions. Furthermore, new method to enhance domain motion was proposed and applied to study conformational transition in
SARS-CoV-2.
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| Academic Significance and Societal Importance of the Research Achievements |
Enzymes are the best catalysts that accelerate chemical reactions. This project clarify the role of disorder and propose a computational approach to study disorder-function paradigm in Enzymes. A new method was also proposed and applied to study structure changes in Spike protein of SARS-CoV-2
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