Molecular Simulation Study On The Action Mechanism Of Molecular Inhibitors Against Protein Misfolding And Aggregation

Protein conformational diseases are numbers of chronic,lethal diseases caused by the conformational change of the normal protein.The protein conformational diseases include Type 2 diabetes,Alzheimer's disease,Huntington disease,Creatzfeldt-Jokob disease,etc.Generally,these diseases are arised when the normal protein undergoes a conformational change into its abnormal ones.It is reported that the proteins which relate to these diseases can aggregate into oligomers and fibers easily,causing cell damage and biological dysfunction.Despite enormous efforts have been made to these diseases,no effective therapy has been found yet.Currently,the main strategy for inhibiting misfolding and aggregation of protein is to stabilize the natural conformation of normal protein or to depolymerize mature fibers.Thus,understanding the inhibitory mechanism of the existing inhibitors is the key to study protein conformational diseases,and it can also provide valuable guidance to the development of new drugs design.In the first part of the thesis,we introduced the protein conformational diseases,such as Parkinson's disease,Type 2 diabetes,and Creutzfeldt-Jakoble disease,to have a better understanding of the progression of the diseases and the impacts on people.And then we summarized the protein misfolding mechanism and the current treatment measures for these diseases.Finally,we described molecular dynamics simulations and their applications in studing protein misfolding and aggragation.The second part of the thesis,we studied the depolymerization of the natural product inhibitor silibinin on human islet amyloid polypeptide(HIAPP).200 ns MD simulations were performed to study the interactions of full-length HIAPP pentamer with silibinin.The results show that silibinin significantly induces the scecondary structure change of pentameric and reduces the stability of it.Based on these,we also identified the possible binding sites of silibinin on the surface of the HIAPP pentamer and the residues that play a critical role in the interaction between the protein and silibinin.The third part of the thesis,we focused on studying the affects of silibinin on the folding progress of HIAPP monomer.We performed replica exchange molecular dynamics simulation of full-length HIAPP monomer with two silibinin molecules during 400 ns.By analyzing MD trajectories,we find that the structure of HIAPP monomer has been changed from random coil to ?-Helix.Additionally,silibinin reduces the exposure of hydrophobicity of the monomer,which may delay the formation of fiber.The fourth part of the thesis,we studied the effects of natural product inhibitor Biochanin A on ?-amyloid protein oligomer.300 ns molecular dynamics simulations were performed for the complex of ?-amyloid decamer and Biochanin A.The results show that Biochanin A disturbs the stability of ?-amyloid decamer and depolymerizes oligomer as well.From the results of clustering analysis and binding free energy calculations,we identified the possible binding sites for Biochanin A.Three residues,including H-Ile41,G-Ile41,and I-Ile41,can form a groove which interacts with aromatic ring of biochanin A by hydrophobic interaction.Thus,the molecule mainly prevents the further aggregation by inhibiting the interaction between layers and layers and depolymerizing the existing oligomers.In this thesis,we investigated the effects of existing small molecular inhibitors on misfolding and aggragation of amyloid protein at the molecular level,and investigated the potential inhibitory mechanism of these small molecular inhibitors.It can provide the theoretical basis and valuable guidance for the treatment of protein conformational diseases and the exploration of effective drugs in the future.