Molecular Dynamics Revealing a Detour-Forward Release Mechanism of Tacrine: Implication for the Specific Binding Characteristics in Butyrylcholinesterase
Butyrylcholinesterase (BChE) is a non-specific enzyme with clinical pharmacological and toxicological significance, which was a renewed interest as therapeutic target in Alzheimer's disease (AD) nowadays. Here, all-atom molecular dynamics simulations of butyrylcholinesterase with tacrine comple...
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Frontiers Media S.A.
2020-08-01
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| Series: | Frontiers in Chemistry |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fchem.2020.00730/full |
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| author | Zhiyang Zhang Fangfang Fan Wen Luo Yuan Zhao Chaojie Wang |
| author_facet | Zhiyang Zhang Fangfang Fan Wen Luo Yuan Zhao Chaojie Wang |
| author_sort | Zhiyang Zhang |
| collection | DOAJ |
| description | Butyrylcholinesterase (BChE) is a non-specific enzyme with clinical pharmacological and toxicological significance, which was a renewed interest as therapeutic target in Alzheimer's disease (AD) nowadays. Here, all-atom molecular dynamics simulations of butyrylcholinesterase with tacrine complex were designed to characterize inhibitor binding modes, strengths, and the hydrogen-bond dependent non-covalent release mechanism. Four possible release channels were identified, and the most favorable channel was determined by random acceleration molecular dynamics molecular dynamics (RAMD MD) simulations. The thermodynamic and dynamic properties as well as the corresponding Detour-forward delivery mechanism were determined according to the classical molecular dynamics (MD) simulations accompanied with umbrella sampling. The free energy barrier of the tacrine release process for the most beneficial pathway is about 10.95 kcal/mol, which is related to the non-covalent interactions from the surrounding residues, revealing the specific binding characteristics in the active site. The residues including Asp70, Ser79, Trp82, Gly116, Thr120, Tyr332, and His438 were identified to play major roles in the stabilization of tacrine in the pocket of BChE, where hydrogen bonding and π-π interactions are significant factors. Tyr332 and Asp70, which act as gate keepers, play crucial roles in the substrate delivery. The present results provide a basic understanding for the ligand transport mechanism depending on the BChE enzymatic environment, which is useful for the design of BChE inhibitors in the future. |
| first_indexed | 2024-12-13T00:30:22Z |
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| issn | 2296-2646 |
| language | English |
| last_indexed | 2024-12-13T00:30:22Z |
| publishDate | 2020-08-01 |
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| spelling | doaj.art-1b43576c001d487cae0ae90e1d16c21c2022-12-22T00:05:20ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462020-08-01810.3389/fchem.2020.00730476749Molecular Dynamics Revealing a Detour-Forward Release Mechanism of Tacrine: Implication for the Specific Binding Characteristics in ButyrylcholinesteraseZhiyang Zhang0Fangfang Fan1Wen Luo2Yuan Zhao3Chaojie Wang4The Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng, ChinaSchool of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou, ChinaThe Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng, ChinaThe Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng, ChinaThe Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng, ChinaButyrylcholinesterase (BChE) is a non-specific enzyme with clinical pharmacological and toxicological significance, which was a renewed interest as therapeutic target in Alzheimer's disease (AD) nowadays. Here, all-atom molecular dynamics simulations of butyrylcholinesterase with tacrine complex were designed to characterize inhibitor binding modes, strengths, and the hydrogen-bond dependent non-covalent release mechanism. Four possible release channels were identified, and the most favorable channel was determined by random acceleration molecular dynamics molecular dynamics (RAMD MD) simulations. The thermodynamic and dynamic properties as well as the corresponding Detour-forward delivery mechanism were determined according to the classical molecular dynamics (MD) simulations accompanied with umbrella sampling. The free energy barrier of the tacrine release process for the most beneficial pathway is about 10.95 kcal/mol, which is related to the non-covalent interactions from the surrounding residues, revealing the specific binding characteristics in the active site. The residues including Asp70, Ser79, Trp82, Gly116, Thr120, Tyr332, and His438 were identified to play major roles in the stabilization of tacrine in the pocket of BChE, where hydrogen bonding and π-π interactions are significant factors. Tyr332 and Asp70, which act as gate keepers, play crucial roles in the substrate delivery. The present results provide a basic understanding for the ligand transport mechanism depending on the BChE enzymatic environment, which is useful for the design of BChE inhibitors in the future.https://www.frontiersin.org/article/10.3389/fchem.2020.00730/fullAlzheimer's diseasetacrinebutyrylcholinesteraserelease mechanism molecular dynamicsMM/GBSAumbrella sampling |
| spellingShingle | Zhiyang Zhang Fangfang Fan Wen Luo Yuan Zhao Chaojie Wang Molecular Dynamics Revealing a Detour-Forward Release Mechanism of Tacrine: Implication for the Specific Binding Characteristics in Butyrylcholinesterase Frontiers in Chemistry Alzheimer's disease tacrine butyrylcholinesterase release mechanism molecular dynamics MM/GBSA umbrella sampling |
| title | Molecular Dynamics Revealing a Detour-Forward Release Mechanism of Tacrine: Implication for the Specific Binding Characteristics in Butyrylcholinesterase |
| title_full | Molecular Dynamics Revealing a Detour-Forward Release Mechanism of Tacrine: Implication for the Specific Binding Characteristics in Butyrylcholinesterase |
| title_fullStr | Molecular Dynamics Revealing a Detour-Forward Release Mechanism of Tacrine: Implication for the Specific Binding Characteristics in Butyrylcholinesterase |
| title_full_unstemmed | Molecular Dynamics Revealing a Detour-Forward Release Mechanism of Tacrine: Implication for the Specific Binding Characteristics in Butyrylcholinesterase |
| title_short | Molecular Dynamics Revealing a Detour-Forward Release Mechanism of Tacrine: Implication for the Specific Binding Characteristics in Butyrylcholinesterase |
| title_sort | molecular dynamics revealing a detour forward release mechanism of tacrine implication for the specific binding characteristics in butyrylcholinesterase |
| topic | Alzheimer's disease tacrine butyrylcholinesterase release mechanism molecular dynamics MM/GBSA umbrella sampling |
| url | https://www.frontiersin.org/article/10.3389/fchem.2020.00730/full |
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