Study On The Mechanical Behavior Of Misfolding Of Cellular Prion

The misfolding of cellular prion protein into pathogenic prion protein can cause neurodegenerative diseases in humans and mammals.The generally accepted theory in this field is that changes in the molecular structure of prion proteins are the cause of prion diseases and their infectivity.Understanding how prion proteins refold from a cellular isoform to a diseasecausing isoform has been among the “ultimate challenges” in molecular biology,biophysics,pathology,and immunology.At present,the two major problems of the mechanism of misfolding of cellular prion protein and the analysis of the structure of pathogenic prion protein have not been resolved.This article will propose the mechanical mechanism of misfolding of cellular prion protein from a mechanical point of view,and predict a scientific and reasonable fourth-rung ?-helix structure model of disease prion protein.The conformational change from cellular prion protein to pathogenic prion protein involves the opening of the alpha helix.It is very difficult to open the helix with stable thermodynamic structure under physiological conditions.Therefore,this article first studies the structural characteristics and stabilization mechanisms of other normal alpha helices to help understand the reasons for the unstable structure of the cellular prion ?1 helix.Using steered molecular dynamics simulations to observe and analyze the changes in the opening process of the ?1 helix structure to obtain the unfolding path of the ?1 helix opening under the action of external force,which helps us understand the role of the ?1-helix in the misfolding process of cellular prion protein.Under the experimental conditions,the addition of polyanions such as heparin under acidic environment will misfold the pathogenic prion protein.However,the state-of-the-art technology cannot obtain the dynamic process of the misfolding of the cell prion protein at this stage.Therefore,the use of rigorous and scientifically reliable molecular dynamics simulation is an effective method.In this paper,molecular dynamics simulation was used to study the evolution of cellular prion structure under high temperature conditions,and the effect of protonation of certain amino acids on the conformational changes of cellular prion protein was studied under acidic conditions,and The parameters of RMS deviation,solvent accessible surface area and so on in the process of conformational change of cellular prion were analyzed.The misfolding process of cellullar prion protein is closely related to Coulomb force,hydrophobic force,hydrogen bonding,thermal disturbance,ion concentration and water molecule shielding effect.According to the experimental results and molecular dynamics simulation,this paper presents a mechanical mechanism of polyanion induced misfolding of cellular prions.Polyanion caused the increase of local hydrogen ion concentration,which destroyed the water molecular shielding of proteins.The Coulomb force between the negative group of polyanion and the positive arginine of ? 1-helix pulled the ? 1 helix apart,which started the cellular prion protein misfolded.Finally,according to the principle of hydrophobic core anhydrous,a fourth-rung ?-helix structure model is proposed.The work of this paper contributes a creative and pioneering theory to solve the problem of the mechanism of cellular prion misfolding into abnormal structure of infectious prion,and has important significance for understanding and studying the prion mechanism,and for the development of drugs for the treatment of prion diseases or reliable specific inhibitors have important guiding significance.