title: Computational insights into the inhibition and destabilization of morin on the oligomer of full-length human islet amyloid polypeptide.
abstract: The aggregation of human islet amyloid polypeptide (hIAPP) is closely related with the occurrence of type 2 diabetes (T2D). Natural flavonoid morin was confirmed to not only inhibit the amyloid formation of hIAPP, but disaggregate its preformed amyloid fibrils. In this study, with the goal of elucidating the molecular mechanism of inhibition and destabilization of morin on the full-length hIAPP(1-37) oligomer, molecular dynamics simulations were performed for hIAPP(1-37) pentamer in the presence and absence of morin. The obtained results show that during the protein-inhibitor interaction, morin can notably alter the structural properties of hIAPP(1-37) pentamer, such as morphology, solvent accessible surface area and secondary structure. Moreover, we identified three possible binding sites of morin on hIAPP, all of which located near the amyloidogenic region of this protein. From the binding free energy calculations, we found that Site II was the most possible one. Further conformational analysis together with energy decomposition showed that the residues His18, Phe23 and Ile26 play a key role in the binding with morin by hydrogen bond, π-π and hydrophobic interactions. The proposal of the theoretical mechanism of morin against hIAPP aggregation will provide valuable information for the development of new drugs to inhibit hIAPP aggregation.
authors.affiliation: School of Pharmacy, Lanzhou University, Lanzhou 730000, China. hxliu@lzu.edu.cn.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou 730000, China.
authors.forename: Shuangyan
authors.initials: S
authors.lastname: Zhou
authors.affiliation: School of Pharmacy, Lanzhou University, Lanzhou 730000, China. hxliu@lzu.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou 730000, China and State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Yao
authors.affiliation: School of Pharmacy, Lanzhou University, Lanzhou 730000, China. hxliu@lzu.edu.cn and State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou 730000, China.
authors.forename: Huanxiang
authors.initials: H
authors.lastname: Liu
authors.affiliation: The Separating Scientific Institute of Lanzhou, Lanzhou, Gansu, China.
authors.forename: Zhide
authors.initials: Z
authors.lastname: Hu
mesh_terms: D001665:Binding Sites; D005419:Flavonoids / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D058228:Islet Amyloid Polypeptide / Q000737:chemistry* / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D066329:Protein Aggregates / Q000502:physiology; D017433:Protein Structure, Secondary; D012997:Solvents / Q000737:chemistry; D055672:Static Electricity; D013816:Thermodynamics; D047309:Flavones
chemical_list: D005419:Flavonoids; D058228:Islet Amyloid Polypeptide; D066329:Protein Aggregates; D012997:Solvents; C008548:morin; D047309:Flavones