Molecular Simulation Study On The Aggregation Of Tau Protein Under The Effect Of Phosphorylation And Small Molecule Inhibitors

Alzheimer’s disease(AD)is a progressive neurodegenerative disorder and the most common dementia.Despite extensive efforts in AD treatment,there is currently no effective cure due to the complex pathological nature of the disease.The misfolding and aggregation of tau protein is closely associated with the occurrence and development of AD.Therefore,it is particularly important to explore its mechanism of action for the treatment of AD.Tau protein is a naturally disordered protein with a variable conformation,and its misfolding process is difficult to observe using traditional experimental methods.Molecular dynamics(MD)simulation can complement the weak points of traditional experimental methods and has significant advantages in exploring protein conformational transitions and the interaction between proteins and inhibitors.In this paper,we investigate the effects of phosphorylation on the structure of Tau protein misfolding and aggregation,as well as the molecular mechanism of small moleculeinduced Tau protein disassembly,using various simulation methods.The content mainly includes two aspects.In the first part,we explored the effects of phosphorylation at different sites on the conformation and aggregation of tau protein.It was found in the experiment that phosphorylation at different sites of tau protein would have different effects on the kinetic behavior of the protein.Phosphorylation at Y310 could inhibit Tau protein aggregation,and phosphorylation at S320 could promote Tau protein aggregation.Here,we selected these important phosphorylation sites to study the effects of phosphorylation on the monomer conformation and aggregation of R3,the important fragment of tau protein.We used discrete molecular dynamics simulations combined with Markov models to investigate the conformational changes in the misfolding of R3 monomers phosphorylated by Y310 and S320.The β-sheet structure is important for the misfolding and aggregation of tau protein.The results showed that R3 monomer can be misfolded to form β-sheet structure,and the formation of β-sheet structure was inhibited by Y310 phosphorylation,while promoted by S320 phosphorylation.Residues involved in the formation of β-sheet structure are changed,including PHF6 at N-terminal,S316-V318 in the middle region,and L325-P332 at Cterminal.In addition,we constructed 16-strand models of R3 to explore effects of phosphorylated Y310 and S320 on R3 spontaneous aggregation,and found that phosphorylated Y310 can promote the formation of α-helix to stabilize R3 structure and prevent its misfolding,thus inhibiting R3 aggregation.Phosphorylated S320 can promote the transformation of R3 monomer into β-sheet structure,thereby raising more monomers to form stable oligomers.The formation of hydrogen bonds and frequent contact between phosphorylated S320 and surrounding residues increase the stability of oligomers.In the second part,we explored the molecular mechanism of depolymerization of tau protein by curcumin and its derivatives.It was found that curcumin could inhibit tau protein aggregation and depolymerize its fibers,and its derivatives C1 and 5d had stronger inhibition on Tau protein.We investigated the molecular mechanism of curcumin and its derivatives inhibiting the aggregation of tau protein by conventional molecular dynamics simulation.The results showed that a pair of tautomer of curcumin and its two derivatives can reduce the stability of PHF6 oligomers by transforming ordered β-sheet structure into disordered Coil structure.The most likely binding site of the small molecules in PHF6 oligomer were also identified.By calculating the free energy of binding,it was found that the binding ability of these small molecules to the PHF6 oligomer was ranked as 5d > C1 > enol-curcumin >keto-curcumin.Hydrogen bonding played an important role in the binding of curcumin and its derivatives to tau protein.In summary,we explore the effects of phosphorylation at different sites on the monomeric conformation and spontaneous aggregation of the important fragment R3 of tau protein,and the molecular mechanism the depolymerization of keto-curcumin,enol-curcumin,curcumin derivatives C1 and 5d depolymerizing PHF6 oligomer.It provides important insights into the influence of phosphorylation on the structure of the tau protein and helps in the development and utilization of curcumin in the treatment of Alzheimer’s disease.It is helpful to understand the pathogenesis of AD and provide theoretical guidance for the development and modification of related therapeutic drugs in the future.