Self-assembly of amyloid-β (Aβ) peptides derived from proteolytic cleavage of amyloid precursor protein (APP) into soluble oligomers and insoluble fibrillar aggregates correlates with the pathology of devastating neurodegenerative Alzheimer’s disease (AD). Recent experimental studies suggest more neurotoxicity of soluble oligomers over the fibrillar aggregates. Hence, it is essential to study Aβ oligomers rather than characterizing the insoluble fibrils. In this study, we have carried out room temperature molecular dynamics simulations of Aβ17-42 pentamer (O5), octamer (O8), decamer(O10), and tridecamer (O13) in aqueous solution. Our results reveal more distortion in the C-terminal strand (strand 2) than N-terminal strand (strand 1). Such relatively more distorted structure at strand 2 may lead to lateral association to form more stable fibril structure. It is observed that relative arrangements between the adjacent monomers remain unaffected with the size of the oligomers although noticeable twisting between the second and the penultimate monomers occurs in higher order oligomers (O10 and O13). Calculation based on molecular mechanics /generalized Born surface area (MM/GBSA) method was performed to compare the relative binding of the adjacent monomers with the central monomer among different oligomers. It is found that nonpolar interaction plays dominant role in stabilizing the oligomers, while electrostatic interaction is unfavorable for the aggregation process. Irrespective of the oligomers, 14 residues (Val-18, Phe-19, Phe-20, Ala-21, Asp-23, Val-24, Ser-26, Asn-27, Lys-28, Ile-31, Ile-32, Leu-34, Met-35, Val-36) contribute significant favorable interaction towards monomer binding of which a major part is provided by side chain interaction. Our results demonstrate that relative monomer binding in the oligomers depends on C-terminal (Val-36 to Ala-42) binding free energy. Importantly, it is shown that unfavorable interaction over 10 kcal mol-1 provided by two C-terminal residues Ile-41 and Ala-42 in O5 and O10 leads to relatively lower binding free energy compared to others. We believe that O5 and O10 may act as the templates for the lateral association because in that case unfavorable C-terminal binding free energy can be compensated by favorable lateral association.

Inter-molecular interactions between the monomers in Aβ17-42 oligomers: A comparative molecular dynamics study

251st National Meeting (2016)

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