Molecular Dynamics Simulations On The Aggregation Of Aβ42Induced By Temperature And Bound With Cu²⁺

A large number of experimental and theoretical works find that the key factor ofneurodegenerative diseases is the intrinsically disordered proteins’ aggregation （such asAlzheimer’s disease, Parkinson’s disease and so on）. But up to now, the full details andmechanisms of these proteins’ have not been known comprehensively and systematically. It is abetter method to understand the aggregation of intrinsically disordered proteins at atomic andmolecular level by molecular dynamics simulation. So we can study the protein aggregation,folding, conformational dynamics and the change of the thermodynamic properties, andinteraction with other substances by molecular dynamics simulation. It is a current frontier topicat home and abroad. The molecular dynamics simulation can not only get the atom’s trajectoryof the protein residues, but it also can observe the various microscopic details in the process ofatomic motion. Currently, it is difficult to detect the intrinsically disordered proteins and get theeffective structures by experiment. So it has important theoretical and practical significance tostudy the intrinsically disordered proteins by molecular dynamics simulation method. It is aneffective supplement and validation method to the experiment.This paper studies temperature and Cu²⁺effects on the intrinsically disordered protein-Aβ42protein in the conformational changes, dynamic and thermodynamic properties, and theirinfluence to the fibrosis aggregation of Aβ42by using the method of molecular dynamicssimulation. The main work is given as follows:（1） The paper overviews the Aβ42protein. It introduces the background about the Aβ42protein and the relationship between Aβ42and Alzheimer’s disease, the external influencefactors to the Aβ protein especially the Aβ42protein. And it is important for us to study theseproteins by using the molecular dynamics simulation method.（2） In this paper, we introduce the basic principle of molecular dynamics simulation, andcompare several integral algorithm of solving the Newton’s second law andexperience/semi-empirical molecular force field. Finally the GROMACS package and GROMOS force field are introduced.（3） The three independent molecular dynamics simulations of Aβ42protein at differenttemperatures300K,340K and380k, are performed using the GROMACS software package andGROMOS43A1force field, respectively. Based on the simulations, we analyze theconformation changes of Aβ42protein and the formation of its secondary structure and tertiarystructure. The results indicate that Aβ42protein has no stable structure and it has the charactersof intrinsically disorder proteins at the different temperatures. It also shows that the structure ofAβ42protein change obviously with different temperature. In addition, there is a changetendency from α-helix to β-sheet at380K. The β-sheet is the basis of Aβ42protein aggregation,and it can form the insoluble fiber.（4） In the paper, the Aβ42protein monomer and Cu²⁺-Aβ42complex are studied by usingmolecular dynamics simulation methods in order to understand the influence of Cu²⁺on Aβ42protein. And then we calculate the secondary structure of complex formation conditions and thedistribution of the main chain of the residue dihedral of Aβ42protein monomer and Cu²⁺-Aβ42complex, analyze the simulation results by conformation clustering, study the heterogeneity ofconformational changes and give surface free energy of the monomer and complex. The freeenergy of its conformation reduced when Cu²⁺combined with Aβ42protein. And Aβ42proteinis more inclined to form β-sheet structure and promote its aggregation.The main content is divided into five chapters. The first chapter is introduction. It mainlyintroduces the influence of Cu²⁺on the Aβ42protein of its structure changes and aggregation,including Aβ42protein’s molecular structure and the role, the external factors that affect Aβ42protein aggregation. The second chapter mainly introduces the basic theory of moleculardynamics simulation, including molecular dynamics simulation, molecular force field, theprinciple of molecular dynamics simulation, GROMACS software, the application anddevelopment of molecular dynamics simulation. The third and fourth chapter is the results andanalysis for Aβ42proteins at different temperatures and bound with Cu²⁺. From the protein’ssecondary structure, the main chain dihedral distribution, free energy, heterogeneity ofconformational and conformation clustering, we can analyze how the temperature and Cu²⁺affect Aβ42protein aggregation. The last chapter summarizes the whole work. It summarizesthe main conclusions of this work, innovation points and the existing problems...