Small Peptide Blockers Impact Of Carbon Nanotubes On The Structural And Thermodynamic Properties Of Amyloid Peptide Molecular Dynamics Study

The folding and aggregation of the protein is a critical program in the field of biophysics and molecular biology in these days. Almost all living actions are performed by the protein. The human neurodegenerative diseases and amyloidosis have aroused public attention in the past few years, and it is supposed that these kinds of diseases are associated with protein misfolding and aggregation. In spite of extensive experimental and theoretical studies, the structures and thermodynamics of the toxic oligomers formed in the early steps of aggregation are still mostly unknown at atomic level of detail not only for the disease-related protein but also for the short peptides identified in the last two decades. This thesis is devoted to investigating the effect of the inhibitor and SWNT on the structures and thermodynamics of the two different amyloidogenic peptides. Here, we propose that the RGTFEGKF inhibitor prevent the aggregation of the Glycophorin A. It showes that SWNT can prevent the aggregation of the Aβ16-22 peptide and also can induce the unfolding of the aggregated Aβ16-22 peptide.The thesis consists of three parts. The first part is a brief introduction of the characters, importance and status of the Aβ16-22 peptides, and the simulation method by computers. The second part is about the effect of the inhibitor and SWNT on the structures and thermodynamics of the protein. The summary of the thesis and prospect of the future research are given in the last part.In chapter 1, the introduction of the characters, importance and status of the protein are briefly introduced. In chapter 2, a brief introduction of the simulation methods and the force fields are given.In chapter 3, we investigate the effect of the RGTFEGKF inhibitor on the aggregation of the Glycophorin A. There is experimental evidence that the transmembrane fragment spanning amino acids 70-86 of glycophorin A, GpA70-86, forms amyloid fibrils and the inhibitor RGTFEGKF prevents GpA70-86 fibril formation at an equimolar ratio. Both of the GpA70-86 and inhibitor peptides contain a GxxxG motif as found in many amyloid proteins such as the Alzheimer's amyloidβ-peptide and prion protein. To explore the intrinsic, early interaction and inhibition mechanism, we have determined the structures of GpA70-86 in the absence and presence of the inhibitor by extensive molecular dynamics simulations in explicit solvent. Consistent with experiments on the fibrils, our simulations show that the two GxxxG motifs interact significantly at the monomer level. However, they go one step beyond by indicating that the inhibitor has a significant impact on the global structure of GpA70-86, but a limited influence on the conformations of the GxxxG motif. Implications of our simulations on amyloid propagation of proteins containing GxxxG motifs are discussed.In chapter 4, we investigate the inhibition mechanism of Aβ16-22 peptide aggregation by carbon nanotubes. The sequence KLVFFAE (Aβ16-22) in Alzheimer's Aβpeptide is thought to be a coreβ-structure that could act as a template for folding other parts of the peptide into fibrillarβ-rich assemblies. Soluble oligomers of Aβpeptide have been implicated in the pathogenesis of Alzheimer's disease as a primary source of neurotoxicity. These oligomers are difficult to characterize experimentally due to their diverse morphologies and rapid conformational fluctuations. Moreover, recent experimental studies show that nanoparticles inhibit the fibrillation of Aβpeptide. However, the nature of the oligomers in solution and the effects of nanoparticles on the structures of these oligomers are still not well understood. To explore the energy landscape of A/β16-22 oligomers and the intrinsic inhibition mechanism of nanoparticles, we have determined the structures of Aβ16-22 oligomers in the absence and presence of the single-walled carbon nanotube (SWNT) by fully atomic replica exchange molecular dynamics simulations (REMD) in explicit solvent. Our simulations totaling 15μs in length show that 1) eight Aβ16-22 peptide chains with random conformation assemble into a diverse ensemble of aggregates including amorphous aggregates, bilayerβ-sheets, andβ-barrels; 2) the introduction of SWNT into the reservoir of random Aβ16-22 peptides prevent the formation ofβ-rich oligomers and increase the population of amorphous aggregates; 3) the addition of SWNT into the prefibrillarβ-rich octamers facilitates the dissociation of theβ-strand and induces a structural transition fromβ-strand to random coil conformation. Detailed analysis of the Aβ16-22--SWNT interactions reveals that both hydrophobic interactions andπ-πstacking play important roles on the aggregation behavior of Aβ16-22 peptides on the SWNT surface.In chapter 5, we give a summary and the expection of future research of the thesis.