Molecular Dynamics Simulation Studies Of The Misfolding And Aggregation Of Proteins Related To Amyloid Diseases

Amyloid diseases are a class of diseases, caused by the misfolding and accumulation of proteins or peptides. Up to now, there are 27 known proteins associated with these diseases involving brain and peripheral protein deposition. Although these proteins do not share sequence homology, their amyloid deposits do share very similar properties and a common pathogenic mechanism. It’s well known that amyloid fibrils are involved in a broad range of neurodegenerative diseases, such as Alzheimer’s disease and prion diseases, as well as some other diseases, such as type Ⅱ diabetes.In the present, there are a lot of limits for experimental techniques to explore the formation of amyloid fibrils on the atomic level, however, MD simulations as a complementary technique have been widely applied in the studies of protein misfolding and aggregations, as they can provide a lot of information difficult to be obtained from experiments.Here, we focused on the misfolding of human prion protein (HuPrP) and the early aggregation stage of IAPP22-28, and the studies can be divided into three aspects:1) The effects of pathogenic mutations on the misfolding of human prion protein. Prion diseases are a type of untreatable and fatal neurodegenerative diseases found in both human and animals. Pathogenesis of prion diseases is associated with the misfolding and aggregation of prion protein (PrP). The conversion of prion protein from its a-helical cellular form (PrPc) to its P-sheet-rich pathogenic scrapie form (PrPSc) is the key event in the origin of prion diseases. However, the molecular basis of this conformational conversion is currently far from being clear and remains an intriguing puzzle waiting to be solved. Here, we used MD simulations to investigate the effects of mutations, T188K/R/A, D202N, E211Q and Q217R, on the structure, dynamics and thermodynamics of the globular domain of PrP, respectively.a) T188K/R/A mutations located at the second native a-helix of human PrP. Although the globular domain is fairly conserved, the three mutations have diverse effects on PrP, including the shift of H1, the elongation of native β-sheet and the conversion of S2-H2 loop to a 310-helix. Different mutations lead to distinct results, indicating the mutants may undergo different pathogenic mechanisms.b) D202N, E211Q, and Q217R mutations located at the third native a-helix of human PrP. The obtained results indicate that these amino acid substitutions have subtle effects on the protein structures, but show large changes of the overall electrostatic potential distributions. We can infer that the changes of PrP electrostatic surface due to the studied mutations may influence the intermolecular interactions during the aggregation process. In addition, the mutations also affect the thermodynamic stabilities of PrP.2) The formation and stability of IAPP22-28 oligomers. Islet amyloid polypeptide (IAPP) is a hormone coexpressed with insulin by pancreatic islet β-cells. The formation of amyloid fibrils by the abnormal aggregation of IAPP is a hallmark of type Ⅱ diabetes. Previous studies suggest that amyloid fibril formation has many characteristics of a "nucleated growth" mechanism. However, the mechanism of how the seed forms and the structural polymorphism of oligomers are still not understood completely. These questions are unique and essential for understanding the pathogenesis and designing the inhibitors against type Ⅱ diabetes. Due to the importance of nuclei in the formation of amyloid, in this work, we present a systematic study with standard molecular dynamics simulation aimed at investigating the characteristics of the nuclei and structural stabilities of hIAPP22-28 oligomers.3) The effects of carbon nanoparticles (NPs) on the aggregation of IAPP22-28. Recently, nanomaterials have been widely applied in biomedical fields. NPs are found to interfere with protein misfolding and aggregation associated with many diseases, however, it is still a debatable issue whether nanoparticles inhibit or promote protein aggregation. In this study, we used MD simulations to explore the influence of three kinds of carbon NPs, graphene, carbon nanotube and C60, on the aggregation behavior of IAPP22-28. Our results indicate these NPs can prevent the formation of β-sheet-rich oligomers of IAPP22-28 in different degrees. The π-π stacking and hydrophobic interactions are dissimilar in each system, which are mainly due to the differences in surface curvature and area. It seems that the adsorption interaction has competitive advantages over the interactions among peptides, and hence the aggregation of IAPP22-28 may be inhibited at the early stage by graphene or SWCNT. Our study can not only enhance the understanding about potential effects of nanomaterials to amyloid formation, but also provide valuable information to develop potential amyloid inhibitors against type Ⅱ diabetes.Our investigation of the effects of disease-associated mutations on PrP can enhance our understanding of how these mutations induce the conversion from PrPc to PrPSc, and further cause prion diseases. In addition, for the IAPP22-28 peptide, the investigation of its aggregation and the stability of its protofibril, as well as the effects on its aggregation, can not only enhance the understanding about potential mechanisms of hIAPP nuclei formation and the extensive structural polymorphisms of oligomers, but also provide valuable information to develop potential β-sheet formation inhibitors against type Ⅱ diabetes.