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Molecular Mechanism Study of the Structure Stability of Amyloid Protein by Peptide Inhibitors

Author: DuWenZuo
Tutor: DongXiaoYan
School: Tianjin University
Course: Biochemical Engineering
Keywords: Amyloid-βpeptide Structure transformation Peptide inhibitor Molecular dynamics simulation Decomposition of binding free energy
CLC: O629.73
Type: Master's thesis
Year: 2010
Downloads: 35
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Along with the development of population aging, Alzheimer’s Disease (AD) receives much attention. Although many studies provide that incidence of AD dues to the aggregation of amyloid-β(Aβ) protein (Aβ40 and Aβ42), there is still deficient information about the pathogenesis of this disease. Therefore it is the bottle-neck phenomenon in prevention and treatment for AD.The aggregation of protein is closely related to protein folding. This process happens during a few hundred nanosecond. Normal experiment techniques are restricted and can’t monitor the structure transformation of Aβat the moment it dessolves. Molecular dynamics simulation (MD) is an effective method in peptide folding research. MD can be used to simulate the folding process of Aβprotein and the inhibition of aggregation at nanosecond time scale and molecular level. Some peptide inhibitors have been provided to inhibit the aggregation and toxic of Aβ42 in some experiments before.In this study, MD is used to research the structure stability of Aβ42 by peptide inhibitors (KLVFF, VVIA, LPFFD) in aqueous solution. The secondary structure of Aβ42, the contact number and H-bond between Aβ42 and inhibitors are analyzed. MM/PBSA method is used in decomposition of binding free energy for each residue in both Aβ42 and peptide inhibitors. The results are classified by essential residue and key residue pairs. The results are shown as follows:1. All the three peptide inhibitors can inhibit the secondary structure transformation of Aβ42 fromα-helix toβ-sheet. The most effective one is KLVFF. A mass of H-bonds which formed between KLVFF and Aβ42 enhance the electrostatic interaction and stable the structure of Aβ42.2. The essential residues and key residue pairs are different among three Aβ42-inhibitors complexes. Therefore the binding free energy and the binding sites of each complex are different. Inhibitor KLVFF binds at the whole N-terminal sequence of Aβ42, and gains the lowest binding free energy. Inhibitor VVIA and LPFFD obtain higher binding free energy, and bind at partial N-terminal sequence of Aβ42.3. The inhibitor KLVFF takes effect to Aβ42 by electrostatic interaction of side chain. VVIA takes effect by electrostatic interaction of backbone. LPFFD takes effect by hydrophobic interaction of side chain. 4. The residues at both ends of peptide inhibitors which make more contribution gain lower binding free emerging than the residues in the middle.5. Acidic amino residue and basic amino residue of inhibitors and Aβ42 are more effective than hydrophobic amino residues in the process of structure stability.The mechanism of Aβaggregation is given by this study at molecular level. The obtained results can provide a theoretical basis for the development and design of Aβinhibitors.

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CLC: > Mathematical sciences and chemical > Chemistry > Organic Chemistry > Natural compounds > α-amino acids,peptides, proteins, nucleic acids > Protein
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