The Study Of Effect Of A53T Mutation On ?-synuclein Misfolding And Aggregation Using Molecular Dynamics Simulation

Protein aggregation is a highly complex process during which amyloid deposits can be formed causing protein conformational diseases such as Parkinson's disease,type 2 diabetes mellitus and Huntington's disease.As the misfolding and aggregation of protein can highly affect the normal biological functions,it is also believed to be the main reason of human neurodegenerative diseases.Thus,it is very important to study the mechanism of misfolding and aggregation of the related protein and explain the relationship between protein aggregation and cytotoxicity.It is also an important prerequisite for the design and development of targeted drug.Molecular dynamics simulation method as a computer-aided means can overcome the limitations of traditional experimental research and provide a way to understand the amyloid formation process at the atomic level.Consequently,in the study of the process of specific protein's misfolding and aggregation,molecular dynamics simulation method can provide valuable information,which cannot be obtained in the traditional experiment.In this paper,we have studied the misfolding and aggregation process of specific protein(?-synuclein)in Parkinson's disease by conventional molecular dynamics simulation and replica exchange molecular dynamics(REMD)simulation.The thesis can be divided into the following four parts:First of all,the first part mainly discussed the relationship between neurodegenerative diseases and protein misfolding.It showed the mechanism of misfolding and aggregation of neurodegenerative disease-related proteins and the idea of drug design,and then it focused on the relationship between ?-synuclein pathogenesis and Parkinson's disease;finally,the molecular dynamics simulation method was described in detail.In the second part of the paper,we focused on the effect of A53 T mutation on the misfolding of ?-synuclein peptide 47-56 by replica exchange molecular dynamics simulation.The wild type and mutant type were subjected to a 200 ns REMD simulation.Through the trajectories analysis which included the determination of the secondary structure content,the comparison of the conformational space characteristics and the distribution of the solvent-accessible surface area,we found that the A53 T mutation may be more likely to be transformed into ?-sheet structure to enhance the tendency of protein aggregation.The third part of this paper,we studied the effect of A53 T mutation on the misfolding and aggregation of ?-synuclein 46-97 pentamer based on molecular dynamics simulation.The wild type and mutant type were simulated for 400 ns long,respectively.The results showed that secondary structure of both the wild type and the mutant type have been changed,and A53 T mutation does make the pentamer have a tendency to shift to the ?-sheet structure,which makes the overall structure more stable.This is because that the mutation increased the binding energy of the whole system leading to the pentamer oligomer more stable.Combined with the work in previous two chapters,it can be concluded that the A53 T mutation will affect misfolding of ?-synuclein and further drive the aggregation process.In the fourth part,we studied that the process of template induction of core peptide by using ?-synuclein 46-97 pentamer as a template by molecular dynamics simulations.The wild type and A53 T mutant type were induced by the corresponding short peptide.Through the 200 ns simulation,it can be concluded that the free monomer on both sides of the A53 T pentamer has a distinct ?-sheet structure,and the mutant type is more efficient in inducing the free peptide into sheet structure with two sides of the adjacent monomer in mutant system adopt ?-sheet structure,while only one was found in the wild type system.This work further confirms that A53 T mutation contributes a lot to aggregation,resulting in a change in the structure of the ?-synuclein that causes the onset of the disease.In this paper,we have carried on the systematic study on the effects of A53T-specific mutation on the misfolding and aggregation of ?-synuclein by molecular dynamics simulation method,and the results can be used to better understand the misfolding and aggregation mechanism of the A53 T mutant ?-synuclein from the atomic level,which provides a theoretical basis to understand the pathogenesis of Parkinson's disease and the design of targeted drug.