Understanding β-Sheets in Alzheimer’s Disease to Confront it

Date
2018-07-10
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Abstract
Based on the β-amyloid peptide (Aβ) hypothesis, Alzheimer’s disease develops when generation and clearance of Aβ become imbalanced. As a result, the peptide goes through structural changes, and establishes aggregates with high β-sheet content. In this thesis, the core hydrophobic region of the peptide, Aβ13-23, designated as “R”, is under investigation. The potency of a series of pseudo-peptides (PP) to block the aggregation of R, as a model of full-length Aβ42, are benchmarked by applying molecular dynamics (MD) and umbrella sampling calculations (MD-US). The effective binding free energy, ΔGeff, is used as a criterion to estimate the inhibitory ability of PPs. The all-L-amino acid PP, SGC1 and the all-D-amino acid SGB1 were predicted to have the highest anti-Aβ aggregation effect. The results are supported by experimental studies. The Electrospray ionization mass spectroscopy on R and one of PPs, named as SGA1, yielded a free energy of dissociation similar to MD-US. The PPs with the highest estimated inhibitory efficacy were further investigated against full-length Aβ42. All the PPs influence the overall structure of the monomeric Aβ. Two methods were exploited to examine the free energy of binding: i) a combination of GROMOS96 53a5 force field gas-phase energies and the Poisson-Boltzmann solvent accessible (PBSA) method, and ii) an improved linear interaction energy (LIE-D) technique. The ranking for PP-Aβ complexes for both methods were almost always consistent with MD-US results on PP-R complexes. The best PPs predicted to inhibit Aβ aggregation are the all-L amino acid inverso SGC1 and the all-D amino acids SGB1 and SGD1. Finally, the Aβ42 dimer conformations were investigated by a total of 9.5 μs MD simulations. The results from cluster analysis and energy calculations suggests that besides the Aβ13-23 (R) region, the C-terminal region of Aβ42 peptide plays an important role in β-sheet formation.
Description
Keywords
Alzheimer's disease, Molecular Dynamics, Amyloid-β Peptide, Structural Analysis, Energy Analysis
Citation
Mehrazma, B. (2018). Understanding -Sheets in Alzheimer’s Disease to Confront it (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/32404