Molecular Dynamics Simulations On The Aggregation Ofα-Synuclein: Cu²⁺-Bound And Metal-Free Forms

Aggregation of proteins in the nerve cells can induce neurodegenerative diseases,including Parkinson’s disease and Alzheimer’s disease etc. In recent years more and moreattentions have been paid to the issues that which proteins’ aggregation will lead to whichdiseases. What kind of conformation changes will lead to aggregation of proteins andwhat are the relationships between aggregation of proteins and abnormal function of nervecells? Which factors will affect the proteins aggregation and what is the mechanism? Howare the kinetic and thermodynamic properties in the process of protein conformationalchange? Although a large number of experimental and theoretical works have forced onthese areas of research, we know that the aggregation of inherently disordered proteinsis a key factor to cause neurodegenerative diseases, but we don’t clearly recognize the fulldetails and mechanisms of proteins aggregation. We believe that the aggregation ofinherently disordered proteins will be understood on atomic and molecular level.The study about molecular dynamics simulation on folding, kinetic andthermodynamic quantities and the interaction with other substances of proteins, is aleading issue currently. Molecular dynamics can not only obtain with the calculation ofresults comparable to the experimental results, but also provide the microscopic structureof the simulation object, particle motion, and a clear image of the relationship betweenthese micro-states and macro materials. Because it’s very difficult to effectively probe thestructure of the inherently disordered proteins from experiments, so the studies frommolecular dynamics simulation of these issues have important theoretical and practicalsignificance. This method can be regarded as a "computer-experiment" and has changedthe relationship between traditional theoretical calculations and experiments.This thesis is based on the molecular dynamics simulation to study the influence ofCu²⁺on theα-synuclein in the structure changes, conformational dynamics and thermodynamic properties, as well as the abnormal aggregation. The main work is givenas follows:（1） We introducedα-synuclein protein from the relationship betweenα-synuclein andParkinson’s disease, molecular structure, physiological function, abnormal aggregationand the influence of Cu²⁺on its structure and the aggregation in order to describe theresearch background.（2） We introduced the basic theory about molecular dynamics of this work. Firstly,the molecular dynamics study of condensed matter systems assumes that the particlemotion complies with the classical dynamics, the Newton’s second law. Then compareseveral integration algorithms for solving Newton’s second law, empirical orsemi-empirical molecular force field. In the end we compared several energy optimizationmethods and introduced the GROMACS package and the GROMOS force field.（3） In this work, both the Cu²⁺-bound and metal-freeα-synuclein（1-17） peptide havebeen simulated with the GROMOS 43A1 force field with the GROMACS package. Thecomplexes with more unfluctuating secondary structures samples moreβ-conformationscompared to the metal-freeα-synuclein（1-17） peptide. The simulations indicate that thecomplexes prefer to sample conformations characterized by larger solvent exposure ofhydrophobic residues than the metal-freeα-synuclein（1-17） peptide. We have found thatthe complexes conformations distribute more compact than the metal-freeα-synuclein（1-17） peptide.This submitted work is divided into five chapters. The first chapter is theintroduction of the influence of Cu²⁺on structure and the aggregation ofα-synuclein; thesecond chapter describes the main theory of the molecular dynamics simulation; chapter 3describes the simulation of systems and methods; the fourth chapter presents the resultsfrom the calculation and analysis of simulation; the last chapter, we summed the wholework.