Abstract
The pathology of Alzheimer’s disease can ultimately be traced to the increased aggregation stability of Aβ42 peptides which possess two extra residues (Ile 41 & Ala 42) that the non-pathological strain (Aβ40) lacks. We have found Aβ42 fibrils to exhibit stronger energies in inter-chain interactions and we have also identified the cause for this increase to be the result of different Ramachandran angle values in certain residues of the Aβ42 strain compared to Aβ40. These unique angle configurations result in the peptide planes in the fibril structures to be more vertical along the fibril axis for Aβ42 which thus reduces the inter-atomic distance between interacting atoms on vicinal peptide chains thereby increasing the electrostatic interaction energies. We lastly postulate that these different Ramachandran angle values could possibly be traced to the unique conformational folding avenues sampled by the Aβ42 peptide owing to the presence of its two extra residues.
Highlights
Despite the obvious clinical importance of both oligomers and fibrils, their structural details at the atomic level have been difficult to characterize[12,25,26,27,28]
That the underlying reason behind increased aggregation attractive interactions and their corresponding superior attractive energies in mature Aβ4 2 fibrils is due to a more vertical orientation of peptide planes within each constituent chain that places backbone carbonyl oxygens and amino hydrogens in closer proximity to each other as evidenced by Ramachandran angle data
Ramachandran angles of Aβ42 peptide chains in the fibril structure indicate that Aβ42 has more well-defined secondary structure characteristics (β-sheet and left-handed α-helix) compared to Aβ4 0
Summary
The pathology of Alzheimer’s disease can be traced to the increased aggregation stability of Aβ42 peptides which possess two extra residues (Ile 41 & Ala 42) that the non-pathological strain (Aβ40) lacks. Prefibrillar/oligomeric aggregate species of Aβ4 2 are recognized as the primary neurotoxic species responsible for neuronal death in Alzheimer’s disease[11,12,13,14,15] there is a recognized appreciable toxicity of Aβ4 2 mature fibrils as has been seen in cell culture experiments[16,17,18,19]. Despite the obvious clinical importance of both oligomers and fibrils, their structural details at the atomic level have been difficult to characterize[12,25,26,27,28] It is known, that in these aggregate species, the constituent peptide chains, or monomers, of both Aβ40 and Aβ42 are held together by hydrogen bonds that stabilize the aggregate formation[29,30,31]. We aim to answer the following two questions: (1) What are the key differences in the inter-chain interaction energetic profiles of Aβ4 0 fibrils and Aβ4 2 fibrils? and (2) What are the underlying conformational changes that are responsible for these differences?
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