Application Of Graphene In Protein Conformation Diseases

These disease which corresponding to protein misfolding,that is,protein misfolding disease,is associated with human’s quality of life.These disease can also severely impair humans health,such as Alzheimer’s disease（AD）,Parkinson’s disease（PD）,typeⅡdiabetes,cataract,and etc.Although the exact molecular mechanisms of AD pathogenesis is still not fully understood,extensive evidence indicates that accumulation of amyloid aggregates（including oligomers,fibrils,and plaques;particularly oligomers）self-assembled by abnormally folded amyloid-beta peptides（Aβ）on neural cell membranes is a critical step in the pathogenesis of the disease.As such,inhibition of monomer fibrillation,dissociation and clearance of amyloid aggregates are considered the possible therapeutic strategies for treating this neurodegenerative disease.Nanotechnology brings us a new way for developing more effective therapies for AD.In this paper,we show both experimentally and theoretically that graphene nanosheets can inhibit Aβmonomer fibrillization,break and clear pre-formed amyloid fibrils,and also vigorously extract large amounts of peptide directly from fibrils.Our atomic force microscopy（AFM）images show that mature amyloid fibrils are cut into pieces by GO sheets,while fluorescence labeling assays illustrate detailed dynamic processes of aggregate inhibition and dissociation starting from monomer peptides and mature amyloid fibrils,respectively.Molecular dynamics simulations revealed that graphene nanosheets can penetrate and extract peptides from the fibrils due to exceptionally strong dispersion interactions between the graphene and peptides.Our findings provide a new sight for drug design of graphene-based nanotherapies for Alzheimer’s disease.There is growing evidence supporting that rather than mature fibrils,the small,partially ordered,oligomers（with relatively lowerβ-sheets content）formed during the early aggregation stage,along with the aggregation process itself,are more likely to be the main toxic agents for cells.Therefore,clearing the small partially ordered oligomers and monomers deposited on the surface of membranes should be an important strategy for curing and preventing PCDs.To validate this hypothesis,extensive all-atom molecular dynamics（MD）simulations were carried out to study the competitive adsorption of NFGAILS peptides and fibrils between a graphene sheet and a membrane.NFGAILS peptide is the core fibrillization segment of human islet amyloid polypeptide(h IAPP_22-28),and is directly involved in type II diabetes mellitus.Many experiments and simulations have proved the similarities between the NFGAILS aggregation cytotoxicity in pancreaticβ-islet cell with respect to its full length peptide.Moreover,we found that the dewetting transition occurred in the interfacial region between graphene and fibrils vigorously assists clearance of（NFGAILS）amyloid fibrils from cell membranes by graphene.