20-29 Fragment Of Human Islet Amyloid Polypeptide Early Aggregation Of Molecular Dynamics Simulation Study

The deposition of proteins in the form of amyliod fibrils and plaques is the characteristic feature of more than 20 degenerative conditions affecting either the central nervous system or a variety of peripheral tissues.As these conditions include Alzheimer's,Parkinson's,and the prion diseases.Much remains to be learned about the mechanism by which the proteins associated with these diseases aggregate and form amyloid structures,and how the latter effect the functions of the organs with which they are associated.A great deal of information concerning these diseases has emerged,however,much of it causing a number of fundamental assumptions about the amyloid diseases to be reexamined.It has also been found resently that aggregation of proteins not associated with amyloid diseases can impair the ability of cell to fuctions to a similar extent as aggregates of protins linked with specific neurodegenerative conditions.Moreover,the mature amyloid fibrils or plaques appear to be substantially less toxic than the prefibrillar aggregates appears to result from an intrinsic ability to impair fundamental cellular processes by interacting with cellular membranes.However,scientists have know little about the mechanisms and details about the early steps of the protein aggregation,althought great efforts have been made,both in experiments and theories.Research on the early steps of protein aggregation may supply the details about formation of oligomers on the atomic level. Although it has been shown that protein aggregation is linked to many diseases,the formation and structures of the intermediate states are still unknown.Because the aggregation process of peptide is complex and the fibrils are insoluble,it is difficult to resolve their structures at the atomic level.Under this circumstance,computer simulations become an sfficient method to investigate the aggregation process occurring in scales of nm and nf.Considerable attention is presently focuses on a group of protein folding disease known as amyloidoses.In these diseases specific peptides or protein fail to fold or to remain correctly folded and then aggregate so as to give rise to 'amyloid' deposits in tissue.Amyloid structures can be recognised because they possess a series of specific tinctorial and biophysical characteristics that reflect a common core structure based on the present of highly organizedβ-sheets.In this thesis,amyloid-forming segment 20-29 from human amylin polypeptide is studied by molecular dynamics simulations. The human islet amyloid polypeptide(hIAPP) or amylin is a 37-residue hormone found as amyloid deposits in pancreatic extracts of nearly all type 2 diabetes patients. The fragment 20-29 of sequence SNNFGAILSS(hIAPP20-29) has been shown to be responsible for the amyloidogenic propensities of the full length protein.Various polymorphic forms of hIAPP20-29 fibrils were described by using FTIR and solid-state NMR experiments:unseeded hIAPP20-29 fibril with out-of-register anti-parallelβ-strands,and two forms of seeded hIAPP20-29 fibril,with in-register anti-parallel or in-register parallelβ-strands.As a first step toward understanding this polymorphism,we explore the equilibrium structures of the soluble hIAPP20-29 trimer,using multiple molecular dynamics(MD) simulations with the OPEP coarse-grained implicit solvent force field.Pritor to trimer simulations,four independent MD simulations,each of 200 ns,are performed on the monomer starting from two distinct states.Than a series of 12 independent MD runs,each of 270 ns,is carried out on the trimer.Both of the simulations suggest that all peptides explore the same conformational space and reach equilibrium states.A good sampling and aggregation mechanism are given.Although,the trimer is found mainly random coil,consistent with the CD signal during the lag phase transition,the central FGAIL residues have a high propensity to form inter-peptideβ-sheets and anti-parallelβ-strands are more probable than parallelβ-strands.One MD-predicted out-of-register anti-parallel three-strandedβ-sheet matches exactly the experimentally-derived unseeded hIAPP20-29 fibril model.Our simulations,however,do not reveal any evidence of in-register parallel or in-register anti-parallelβ-sheets as reported for seeded hIAPP20-29 fibrils.All these results indicate that fibril polymorphism is partially encoded in a trimer.