Computational Study on the Assembly of Amyloid β-Peptides in the Hydrophobic Environment

Abstract

Fibrillated aggregation of amyloid β (Aβ) peptides is a potential factor causing toxic amyloid deposition in neurodegenerative diseases. A toxic fibril formation of Aβ is known to be enhanced on the ganglioside-rich lipid membrane containing some amounts of cholesterol and sphingomyelin. This ganglioside-rich membrane is supposed to provide a hydrophobic environment that promotes the formation of Aβ fibrils. Molecular dynamics simulations were carried out to investigate the structure of Aβ complex in the hydrophobic solution composed of dioxane and water molecules. The Aβ conformation was contrasted to that in the aqueous condition by executing multiple computational trials with the calculation models containing one, four, or six Aβ peptides. The conformation was also compared between the calculations with the 42-mer (Aβ 42) and 40-mer (Aβ 40) peptides. The simulations for Aβ 42 demonstrated that Aβ peptides had a tendency to stretch out in the hydrophobic environment. In contrast, Aβ peptides were closely packed in the aqueous solution, and the motions of Aβ peptides were suppressed significantly. The N-terminal polar domains of Aβ peptides tended to be positioned at the inside of the Aβ complex in the hydrophobic environment, which supported the C-terminal domains in expanding outward for inter-molecular interaction. Since Aβ peptides were not tightly packed in the hydrophobic environment, the total surface area of the Aβ complex in the hydrophobic solution was larger than that in the aqueous one. The simulation for Aβ 40 peptides also showed a difference between the hydrophobic and aqueous solutions. The difference was compatible with the results of Aβ 42 in the structure of the Aβ complex, while the C-terminal outward expansion was not so distinct as Aβ 42 peptides.

Cholesterol as a key player in amyloid β-mediated toxicity in Alzheimer’s disease

“…AFM visualization and MD simulations demonstrated that cholesterol in the lipid bilayer significantly increased Aβ42 surface aggregation, but not membrane penetration, at monomer concentrations as low as nM. These results suggest the importance of membrane lipids for the local concentration, clustering, and conformation change of Aβ into a β-structure-rich form of amyloid peptides (Drolle et al, 2012 ; Qu et al, 2019 ; Banerjee et al, 2021 ). It is speculated that the AD-associated elevation of cholesterol levels in the PM may increase the likelihood of membrane-dependent Aβ42 aggregation (Banerjee et al, 2021 ).…”

“…After interaction with a membrane, Aβ can damage the bilayer through a “carpeting effect” in which the amyloid disrupts membrane integrity by covering its surface, it can exert detergent-like effects, or amyloid peptides can self-organize into transmembrane ion channels (Figure 1 ; Williams and Serpell, 2011 ; Cecchi and Stefani, 2013 ; Press-Sandler and Miller, 2018 ; Sciacca et al, 2018 ). Due to the presence of different nucleation centers, the nature of the lipid membrane determines the state of the peptide, which is closely linked to the processes of Aβ assembly and toxicity (Ding et al, 2012 ; Cecchi and Stefani, 2013 ; Pannuzzo, 2016 ; Bera et al, 2019 ; Qu et al, 2019 ).…”

“…Red—amyloid β, yellow—membrane lipids, purple—cholesterol. The scheme was prepared according to Eckert et al ( 2001 ); Yip et al ( 2002 ); D’Errico et al ( 2008 ); Abramov et al ( 2011 ); Zhao et al ( 2011 ); Drolle et al ( 2012 ); Yu and Zheng ( 2012 ); Fantini et al ( 2014 ); Seghezza et al ( 2014 ); Brown and Bevan ( 2016 ); Press-Sandler and Miller ( 2018 ); Staneva et al ( 2018 ); Fabiani and Antollini ( 2019 ); Qu et al ( 2019 ); and Banerjee et al ( 2021 ).…”

Computational Screening of Inhibitory Compounds for SARS-Cov-2 3CL Protease with a Database Consisting of Approved and Investigational Chemicals

“…23) MM calculation is useful for analyzing intermolecular interactions such as antibody recognition of antigens 24,25) and the amyloid peptide addiction to a membrane surface. 26) MM calculation is also useful for analysis of compound-protein interactions 27) and is utilized for the molecular design of candidate inhibitors. 28) The compounds selected by the computer screening were examined in experiments for their potency to block the enzymatic activity.…”