Dissecting the Inhibitory Mechanism of the αB-Crystallin Domain against Aβ₄₂ Aggregation and Its Effect on Aβ₄₂ Protofibrils: A Molecular Dynamics Simulation Study

Abstract

Alzheimer′s disease (AD) is related to the misfolding and aggregation of amyloid-β (Aβ) protein, and its major pathological hallmark is fibrillary β-amyloid plaques. Impeding the formation of Aβ β-structure-rich aggregates and dissociating Aβ fibrils are considered potent strategies to suppress the onset and progression of AD. As a molecular chaperone, human αB-crystallin has received extensive attention in the inhibition of protein aggregation. Previous experiments reported that the structured core region of αB-crystallin (αBC) exhibits a better preventive effect on Aβ aggregation and toxicity than the full-length protein. However, the molecular mechanism behind the effect of inhibition remains mostly unknown. Herein, we carried out six 500 ns molecular dynamics (MD) simulations to investigate the inhibitory mechanism of αBC on Aβ 42 aggregation. Our simulations show that αBC greatly impedes the formation of β-structure contents. We find that the binding of αBC to the Aβ 42 monomer is driven by polar, hydrophobic, and H-bonding interactions. To explore whether αBC could destabilize Aβ 42 protofibrils, we also carried out MD simulations of Aβ 42 protofibrils with and without αBC. The results show that αBC interacts with three binding sites of the Aβ 42 protofibril, and the binding is mainly driven by polar and H-bonding interactions. The binding of αBC at these three sites has a preferred dissociation effect on the β-structure content, kink angle, and K28-A42 salt bridges. Overall, this study not only discloses the molecular mechanism of αBC against Aβ 42 aggregation but also demonstrates the disruption effects of αBC on Aβ 42 protofibrils, which yields an avenue for designing anti-AD drug candidates.

SEVI Inhibits Aβ Amyloid Aggregation by Capping the β-Sheet Elongation Edges

“…With the β-sheet edges of Aβ monomers, oligomers, and proto-fibrils occupied by the highly charged SEVI, the corresponding growth to higher-molecular-weight oligomers, nucleation of proto-fibrils, and rapid fibril elongation could be inhibited. It is worth noting that the capping strategy to prevent edge-to-edge aggregation has been observed not only with SEVI but also with other amyloid inhibitors. , For instance, αB-crystallin has been found to inhibit Aβ aggregation by capping the β-sheet elongation edge. , Furthermore, a similar “negative design” approach that involves strategically positioning charged residues at the β-sheet edges has also been used in the design of amyloid inhibitors. , Mechanistic insights obtained from our systematic computational studies may aid in the development of novel therapeutic strategies to modulate the pathological aggregation of amyloid protein in degenerative diseases.…”

“…32,33 For instance, αB-crystallin has been found to inhibit Aβ aggregation by capping the β-sheet elongation edge. 34,84 Furthermore, a similar "negative design" approach that involves strategically positioning charged residues at the βsheet edges has also been used in the design of amyloid inhibitors. 85,86 Mechanistic insights obtained from our systematic computational studies may aid in the development of novel therapeutic strategies to modulate the pathological aggregation of amyloid protein in degenerative diseases.…”

Inhibitive and Destructive Mechanisms of Chronic Traumatic Encephalopathy-Related R3-R4 Tau Peptide Chains and Protofibril by Epigallocatechin Gallate: Evidence from Molecular Dynamics Simulation

“…Dominant Binding Sites and Interactions of EGCG on the CTE-Related R3-R4 Tau Dimer. Recent studies 61,62 indicate that the atomic contact number can well reflect the binding preference of the ligand on the amyloid protein. Therefore, we calculated the MC/side chain (SC) contact number and H-bond number between EGCG and the dimer to identify the dominant binding sites of EGCG on the CTErelated R3-R4 tau dimer.…”

Effect of Terahertz Waves on the Structure of the Aβ42 Monomer, Dimer, and Protofibril: Insights from Molecular Dynamics Simulations

“…However, due to available experimental technologies, it is still challenging to systematically visualize the structure and self-assembly process of Aβ42 peptides under various conditions. Molecular simulations, on the contrary, may offer some useful information from the microscopic view, which have been extensively employed in this field. − For example, Fatafta et al performed microsecond-scale molecular dynamics (MD) simulations to explore the dynamic behavior of the Aβ42 dimer in different environments and found that the secondary structure of the Aβ42 dimer exhibited a transition from a random coil to a β-sheet in solution, but it was inhibited to some extent in the presence of lipid bilayers. Man et al reported an all-atom MD simulation study on Aβ42 dimers, trimers, and tetramers.…”