Molecular Dynamics Study On The Disruption Of β-amyloid Aggregation By Norepinephrine

Objectives: Objectives: With the increase of human life expectancy,the prevalence of Alzheimer’s disease(AD),a degenerative disease caused by the central nervous system,is rising sharply.Fiber aggregation and deposition plaques caused by Amyloidβ-protein(Aβ)in the brain are the main signs of pathological diagnosis of AD.Due to the complex pathogenesis of AD and the special protection of the blood-brain barrier to the central nervous system,the drug development of AD has been blocked for a long time.Therefore,the search for effective non-drug treatment methods to delay the progression of the disease and prevent the occurrence of the disease has received extensive attention.As a globally recognized health behavior,exercise can reduce the risk of death and promote physical and mental health.It has been confirmed that exercise can improve the cognitive function,memory ability and emotional state of the elderly,improve the early symptoms of AD,and thus delay the onset of AD.The strong stimulation of exercise on the body can promote the level of Norepinephrine(NE),a bioactive substance,and the rising rate is positively correlated with the intensity of exercise.NE can be naturally produced in the brain and is not affected by the blood-brain barrier.It projects from the locus coeruleus axons to various brain regions and can interact with Aβ,which is A natural small molecule inhibitor.From the perspective of exercise promoting health,this study used molecular dynamics simulation to explore the microscopic effect and destruction mechanism of NE on Aβkey aggregates,and analyzed the potential mechanism of exercise intervention in AD,so as to provide theoretical basis and new insights for exercise to prevent AD and delay the pathological progress of AD.Methods: Literature review was used to provide theoretical basis for research and experimental design,and molecular dynamics simulation was used to explore the microscopic mechanism of NE destroying Aβ key aggregates.The Gromacs2018.4program was used to construct the simulation system: Aβ tetramer was used as the study control group,Aβ tetramer +NE molecule was used as the study experimental group,and the concentration molar ratio was 1:5.The AMBER99SB-ILDN force field used for biomacromolecule simulation was selected for the two groups of simulation systems,and the NE molecule was set by the GAFF force field.The simulated ecological environment of the two groups was consistent.In this study,the two systems were simulated three times for 500 nanoseconds.Visual merchandising(VMD)program was used to view the simulation trajectory and intercept the schematic diagram,and Gromacs’ s own program and third-party programs were used to process and analyze the data.Origin lab software was used for secondary analysis of the data,SPSS 26.0 software was used for the difference test of the indicators,and Adobe Illustrator 2021 and Excel 2019 software were used for the charting of the results.Results:(1)Compared with the control group,the Cα-RMSD(P<0.001),especially in the Nterminal D1-H14 amino acid region(P<0.001).(2)The proportion of secondary structure of Aβ fibrils showed that the probability ofβ-sheet,the key toxic structure in the experimental group,was 2.06% less than that in the control group(from 61.36 to 59.30%).The probability of Coil+Bend+Turn in the experimental group increased by 2.07% compared with that in the control group(from38.64 to 40.70%).(3)The addition of NE weakened the contact between amino acids of Aβ fibrils,among which the H6-E11 hydrogen bond,K28-A42 salt bridge,and the hydrophobic core A2/F4/L34/V36 and L17/F19/I31 residues were significantly reduced.(4)Can be combined with A beta binding sites and mode,according to the results of main and E3 / R5 / H6 / E11 / H13 / F20 / E22 perhaps A residue,and E3 / D7 / E11 /E22 / perhaps A residue formed at least one hydrogen bond contact,and H6,H13 and F20 residues formed π-π stacking contact.Conclusions:(1)This study found that in the simulation system with the presence of NE,the SASA value of Aβ fibrils increased,the Angle of L-shaped structure increased,and the configuration of Aβ protein changed significantly.The change of protein configuration destroys the structural stability of Aβ fibrils and reduces the β-sheet structural content of Aβ fibrils,which is not conducive to further aggregation of Aβinto mature fibrils that cause damage to the brain.(2)this study provides the movement to prevent and delay the progression to AD micro-level explanation and information,as the science exercise therapy provides theoretical basis and practical basis.