Reaction Mechanism of Actin ATP Hydrolysis Studied by QM/MM Calculations

doi:10.1007/s40242-024-4089-2

Chemical Research in Chinese Universities ›› 2024, Vol. 40 ›› Issue (5): 849-855.doi: 10.1007/s40242-024-4089-2

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Reaction Mechanism of Actin ATP Hydrolysis Studied by QM/MM Calculations

WANG Yiwen¹, LIN Lirui^2,3, XU Li-Yan^4,5,6, LI En-Min^1,4, DONG Geng^1,3,6

1. Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, P. R. China;
2. Department of Bioinformatics, Shantou University Medical College, Shantou 515041, P. R. China;
3. Medical Informatics Research Center, Shantou University Medical College, Shantou 515041, P. R. China;
4. Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou 515041, P. R. China;
5. Cancer Research Center, Shantou University Medical College, Shantou 515041, P. R. China;
6. Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou 515041, P. R. China

Received:2024-04-10 Online:2024-10-01 Published:2024-09-26
Contact: LI En-Min,nmli@stu.edu.cn E-mail:nmli@stu.edu.cn
Supported by:
This work was supported by the National Natural Science Foundation of China (No.21907063),the Li Ka-shing Foundation,China (No.LD0101),the 2020 Li Ka-shing Foundation Cross-Disciplinary Research Grant,China (No.2020LKSFG07B),the Innovation Team Grant of Department of Education of Guangdong Provice,China (No.2021KCXTD005) and the Shantou University Medical College (SUMC) Scientific Research Initiation Grant,China (No.510858063).

Abstract

Abstract: Actin fibers are an important part of the cytoskeleton, providing vital support for the plasma membrane. This function is driven by its ATPase (ATP: adenosine triphosphate) activity, i.e., ATP+H₂O→ADP+P_i. This seemingly simple reaction has attracted much attention because the hydrolysis of ATP provides energy to support life processes. However, the reaction mechanism of ATP hydrolysis in actin is not clear. In order to gain deep insights into the functions of actin, it is essential to elucidate the reaction mechanism of the actin ATP hydrolysis. In this paper, we have studied the reaction mechanism of the ATP hydrolysis in actin by the combined quantum mechanical and molecular mechanics (QM/MM) calculations. Our results show that 1) bond cleavage of the P_γ—OS of ATP and bond formation between oxygen of the lytic water and P_γ atoms take place simultaneously, and this is the rate-limiting step of the hydrolysis; 2) the proton on the lytic water transfers to the phosphate to form H₂P_γO₄^- via one bridge water. The energy barrier of the complete reaction is 17.6 kcal/mol (1 kcal=4.184 kJ), which is in high agreement with the experimental value.

Key words: Actin, Adenosine triphosphate (ATP) hydrolysis, Quantum mechanical and molecular mechanics (QM/MM), Reaction mechanism

WANG Yiwen, LIN Lirui, XU Li-Yan, LI En-Min, DONG Geng. Reaction Mechanism of Actin ATP Hydrolysis Studied by QM/MM Calculations[J]. Chemical Research in Chinese Universities, 2024, 40(5): 849-855.

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Reaction Mechanism of Actin ATP Hydrolysis Studied by QM/MM Calculations

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