Atomistic Molecular Simulation Study Of The Amyloid Proteins

The misfolding of protein or peptide will lead to amyloid aggregation. The amyloid fibril consists of cross-β conformer and is related to a series of diseases. Aβ is a short peptide with37-43residues. Its accumulation in the brain is the key pathological feature of the Alzheimer’s disease. The aggregation process of Aβ is very complicated and modulated by many factors. This thesis reports our studies on the mechanism of some relevant effects.The Aβ is unstructured in aqueous solvent but rich of β-strands in aggregation conformation. Therefore, the monomeric Aβ undergoes a conformational transformation during the formation of fibrillar. The preformed aggregation-prone conformation can evidently speed up the elongation of the fibrils as if it could be provided as templates of β-strand structure. Using atomistic molecular simulations, we studied the template effects of the preformed structure. The analysis of secondary structure propensity implies that the template with the cross-β structure could induce the formation of β-strand conformations for the monomeric Aβ while the helix template has no such effect. When the template is changed into hIAPP or polyalanine, the enhancement could still be observed. This result shows that this effect strongly depends on the secondary structure of the template peptides but is insensitive to the sequence details. Further analysis shows that the template tends to disrupt the intrapeptide interactions of the monomeric Aβ and reduces the energy frustration, therefore promoting the fibrillar aggregation.. These results uggest that the hydrophobic interactions play a crucial role, providing a better understanding on the molecular mechanism of the docking stage of aggregation.The conformational distribution of the Aβ monomer and aggregation process could be affected by many physical and chemical factors, such as pH environment and metal ions. N-terminal segment, which includes residues1-16, is disordered in the fibrillar aggregates. Previous simulation works usually overlooked the effect of N-terminal disordered parts on the aggregation and removed it directly in the simulations. Noticeably there are three histidines in the N-terminal disordered region. These histidines are sensitive to pH and metal ions. We perform replica exchange molecular dynamics simulation with different charge states of histidines. Our simulation results demonstrated that the N-terminal disordered part can affect the conformational distributions of the residues17-42. The non-specific contacts and salt bridge could be modulated by the charge states of the histidines. These results are important in understanding the mechanism of the pH value and metal ion regulated A (3fibrillar aggregation.