Molecular Docking and Molecular Dynamics Studies on Selective Synthesis of α-Amyrin and β-Amyrin by Oxidosqualene Cyclases from Ilex Asprella
| Autor: | Weiwen Chen, Zhixue Wu, Kui Wang, Hui Xu, Meiling Wang, Ruoting Zhan, Zaoyuan Kuang, Jiangyong Gu, Ren Zhang, Fengxue Zhang |
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| Rok vydání: | 2019 |
| Předmět: |
Amyrin
Molecular model Stereochemistry Ilex 010402 general chemistry 01 natural sciences Article Catalysis lcsh:Chemistry Inorganic Chemistry Molecular dynamics Residue (chemistry) chemistry.chemical_compound Protein structure Ilex asprella Homology modeling Oleanolic Acid Physical and Theoretical Chemistry lcsh:QH301-705.5 Intramolecular Transferases Molecular Biology Spectroscopy Plant Proteins selective synthesis Binding Sites molecular modeling 010405 organic chemistry Chemistry amyrin Organic Chemistry General Medicine 0104 chemical sciences Computer Science Applications Molecular Docking Simulation lcsh:Biology (General) lcsh:QD1-999 residue-product interaction oxidosqualene cyclase Pentacyclic Triterpenes Protein Binding Ramachandran plot |
| Zdroj: | International Journal of Molecular Sciences International Journal of Molecular Sciences, Vol 20, Iss 14, p 3469 (2019) Volume 20 Issue 14 |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms20143469 |
| Popis: | Amyrins are the immediate precursors of many pharmaceutically important pentacyclic triterpenoids. Although various amyrin synthases have been identified, little is known about the relationship between protein structures and the constituent and content of the products. IaAS1 and IaAS2 identified from Ilex asprella in our previous work belong to multifunctional oxidosqualene cyclases and can produce &alpha amyrin and &beta amyrin at different ratios. More than 80% of total production of IaAS1 is &alpha amyrin while IaAS2 mainly produces &beta amyrin with a yield of 95%. Here, we present a molecular modeling approach to explore the underlying mechanism for selective synthesis. The structures of IaAS1 and IaAS2 were constructed by homology modeling, and were evaluated by Ramachandran Plot and Verify 3D program. The enzyme-product conformations generated by molecular docking indicated that ASP484 residue plays an important role in the catalytic process and TRP611 residue of IaAS2 had interaction with &beta amyrin through &pi &ndash &sigma interaction. MM/GBSA binding free energy calculations and free energy decomposition after 50 ns molecular dynamics simulations were performed. The binding affinity between the main product and corresponding enzyme was higher than that of the by-product. Conserved amino acid residues such as TRP257 TYR259 PHE47 TRP534 TRP612 and TYR728 for IaAS1 (TRP257 PHE473 TRP533 TRP611 and TYR727 for IaAS2) had strong interactions with both products. GLN450 and LYS372 had negative contribution to binding affinity between &alpha amyrin or &beta amyrin and IaAS1. LYS372 and ARG261 had strong repulsive effects for the binding of &alpha amyrin with IaAS2. The importance of Lys372 and TRP612 of IaAS1, and Lys372 and TRP611 of IaAS2, for synthesizing amyrins were confirmed by site-directed mutagenesis. The different patterns of residue&ndash product interactions is the cause for the difference in the yields of two products. |
| Databáze: | OpenAIRE |
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