Molecular Dynamics Simulation Of Cross-seeding Between Pathogenic Proteins Of Alzheimer’s Disease-aβ And Tau

Alzheimer’s disease(AD)is a representative type of neurodegenerative disease.Patients will show symptoms of dementia and eventually lose the ability of personal life.Related studies have shown that abnormal aggregation of amyloid and neuronal cell death induced by aggregates are the main causes of AD.Fully understanding the mechanism of amyloid misfolding and aggregation is of great significance for the molecular mechanism of AD and other neurodegenerative diseases and the development of therapeutic drugs.Some in vivo and in vitro experiments have shown that different types of amyloid interact with each other to affect the aggregation process of amyloid.This phenomenon between amyloids is called cross-seeding.The pathogenic proteins of AD:amyloid-β(Aβ)and Tau also cooperate and affect their aggregation process,but the specific mechanism of the cross-seeding is not clear.In this article,molecular docking and molecular dynamics(MD)simulation methods were used to study the cross-seeding process between Aβ and Tau oligomers from the perspective of atom and molecule.The protein-protein docking method was used to find the conformation of Aβ-Tau hybrid oligomers with different binding regions under the effect of cross-seeding,avoiding subjective factors introduced by self-matching.Four types of hybrid oligomer conformations were obtained by molecular docking:double-layer,block,singlelayer,and part-in.Among them,the part-in conformation is a significant composite conformation that has not been studied.Representative Aβ-Tau hybrid oligomers with different structures were selected,and MD simulation was used to study the property related to structure and binding free energy of complete Aβ42 and the R3 and R4 regions of Tau which were rarely reported in cross-seeding.The MD simulation results showed that the overall structure of the part-in conformation was stable in all representative conformations.Among them,there was the strongest binding energy and the tightest binding between Aβ and Tau.Further research found that the structure of the Aβ and Tau pentamers in the part-in conformation was transformed in the MD simulation.This change made the part-in conformation more hydrophobic and more compact.The analysis of the binding energy and interaction force in the part-in region and other region revealed the essence of the part-in composite structure:this conformation is the average of the single-layer conformation component and the double-layer conformation component.Those above studies have played a certain guiding role in understanding the mechanism of cross-seeding between amyloid proteins.