Flexible N‐Termini of Amyloid β‐Protein Oligomers: A Link between Structure and Activity?

Abstract

Revised amyloid cascade hypothesis of Alzheimer′s disease (AD) states that amyloid β‐protein (Aβ) triggers the disease through formation of soluble low molecular weight (LMW) assemblies, called oligomers, which are challenging to characterize experimentally as well as computationally due to their heterogeneous and polymorphic nature, lack of ordered structure, and short lifetimes. Recent findings challenge the view of Aβ oligomers as exclusively toxic entities by revealing their dual, protective and disruptive nature in the context of immune response and AD, respectively. In this review, the understanding of Aβ oligomer formation and structure is discussed from the AD perspective. The structure‐activity relationship (SAR) that implicates flexible, solvent exposed N‐termini of Aβ oligomers, observed in computer simulations, in mediating their toxic as well as protective activity is proposed.

Elucidating the Role of Hydroxylated Phenylalanine in the Formation and Structure of Cross-Linked Aβ Oligomers

“…To examine the effect of X-linking on free energy landscapes of Aβ oligomers, we calculated PMFs of X-linked and non-Xlinked Aβ 40 and Aβ 42 monomers, dimers, trimers, and hexamers using two reaction coordinates: the N-CM distance and the hydrophobic CG-SASA as described in the Methods section (Figure 15). The N-CM distance was selected because previous DMD4B-HYDRA studies of Aβ 40 and Aβ 42 oligomers revealed distinct alloform-specific NTR conformations 23 and the hydrophobic CG-SASA quantifies the ability of the conformation to shield hydrophobic amino acids from the solvent.…”

“…50 It has been thus proposed that Xlinked Aβ 40 and Aβ 42 oligomers may be the proximate neurotoxic species in AD. 23 DMD4B-HYDRA simulations of Aβ 40 and Aβ 42 oligomer formation have been shown to capture alloform-specific oligomer size distributions and distinct structural features of Aβ 40 and Aβ 42 oligomers. 25,30 Recently, the effect of simple Xlinking via tyrosines on Aβ 40 and Aβ 42 oligomer formation and structure was explored using the DMD4B-HYDRA approach.…”

“…20 Williams et al also reported that X-linking stabilizes Aβ oligomers and inhibits their conversion into fibrils, which prolongs membrane disruption mediated by Aβ oligomers. If the CHICUP process occurs in the AD brain, Aβ oligomers Xlinked by CHICUP may represent the proximate neurotoxic species in AD 23 and examining the effect of X-linking on Aβ oligomer formation and structure may provide important insights relevant to AD. Molecular dynamics (MD) offers a way to glimpse into early stages of oligomer formation and structure of full-length Aβ 24 as well as other intrinsically disordered proteins.…”

Cross-Linked Amyloid β-Protein Oligomers: A Missing Link in Alzheimer’s Disease Pathology?

“…It is important to elucidate atomistic details of Aβ oligomer structure and identify the structural aspects that could mediate their activity, in both health and disease. Molecular dynamics (MD) provides atomistic structural information about Aβ oligomers, which complements experimental findings by offering mechanistic insights into the oligomer formation and structure that are not accessible to experimental studies. , Despite significant computational progress in the past two decades, time evolution of Aβ aggregation from initially monomeric peptides is still not easy to study by fully atomistic explicit-solvent MD.…”

“…Structural analysis of cross-linked Aβ oligomers reported by Zhang et al revealed increased solvent exposure at the Nterminal region relative to the respective non-cross-linked conformations, 70 which has been previously associated with increased oligomer toxicity. 50 Experimental results on stabilization of Aβ oligomers through CHICUP 34 and the follow-up computational studies exploring the cross-linking mechanism 68,70 provide important insights into the cross-linking process and elucidate the role of phenylalanine hydroxylation in cross-linking under oxidative stress conditions.…”