Study On The Action Mechanism Of Small- Molecular And Peptide Inhibitors Against The Islet Amyloid Polypeptide Aggregation

Type Ⅱ diabetes is most widespread in four types of diabetes, which is closely related with the misfolding and aggregation of human islet polypeptide (hIAPP). This kind of disease resulted from protein’s misfolding and aggregation, is called conformational disease. Developing the inhibitors inhibiting protein’s misfolding and aggregation has always been believed as one of the most promising strategies against protein conformational disease. At present, amyloid inhibitors mainly contain two categories:small molecules and peptides. However, their action mechanisms are still unclear. Understanding the action mechanism of these inhibitors is of great importance for designing new-type inhibitors henceforth. Based on this, with the molecular dynamics (MD) simulation, the inhibitory mechanisms of two natural small-molecular and one peptide- inhibitors against the islet polypeptide aggregation were investigated.The first section of the present thesis firstly described the protein conformational diseases, using the Alzheimer’s disease, Parkinson’s disease and type Ⅱ diabetes as examples, then introduced the mechanism of amyloid aggregation and the existing control measures, and finally introduced the theoretical principle of MD simulation and the used important analysis methods in this thesis.The second section is to study the influence of representatively natural small-molecular inhibitor EGCG on the islet polypeptide oligomers. The pentamer and decamer of hIAPP complexed with EGCG were simulated, respectively. The analyzed results show that EGCG is able to notably interrupt the structural stability of these two oligomers. On the most possible S1 site, EGCG exerts the inhibitory activities mainly through the strong hydrogen bond, hydrophobic and π-π stacking interactions.In the third section, combining MD simulation and molecular mechanics generalized born surface area (MM/GBSA) methods, the inhibitory and remodeling basis of another natural polyphenol inhibitor resveratrol on the oligomers of hIAPP was explored. As for the initially identified two possible binding sites (Site I and Site Ⅱ), the calculated results of MM/GBSA show that resveratrol has the stronger binding affinity with Site Ⅱthan Site Ⅰ, therefore Site Ⅱ is more likely to be the binding site of resveratrol on islet polypeptide.In the fourth section of this thesis, with the aim of illuminating the molecular basis of islet polypeptide central peptide analogue against the process of protein oligomerization, NFGAIL-GI (The main-chain NH of Gly24 and Ile26 were methylated) was chosen as the peptide inhibitor and NFGAIL octamer was used as the homologous oligomer. During the MD simulation, a dissociative monomer is placed around this octamer. Results show that the difference of bilateral chemical environment of islet polypeptide octamer affects the assembly of dissociative monomer with this octamer. The chain-D direction of β-sheet layer is more favorable for the growth and extension of amyloid fibrils. Furthermore, in the same direction, the peptide inhibitor NFGAIL-GI achieves the inhibition against monomer’s assembly at the end of β-sheet layer.The whole thesis explored the inhibitory basis of small molecule and peptide inhibitors against hIAPP aggregation on the atomic level, and the obtained results would provide valuable guide for discovering and designing the new drugs against amyloid assembly.