Effect of pH on Aβ₄₂ Monomer and Fibril‐like Oligomers—Decoding in Silico of the Roles of pK Values of Charged Residues

Abstract

Amyloid beta-peptide (Aβ) is the key to developing Alzheimer's disease. Experiments have confirmed that different acidity influences directly not only the structural morphology and population of Aβ oligomers, but also the toxicity. The atomic-level association between the pH, charged residues, and Aβ properties remains obscure. Herein, conformational changes of Aβ monomer, fibril-like trimer, and pentamer in the medium pH range of 4.0-7.5 are studied. The results reveal that, as the pH changes from 7.5 to the isoelectric pH, His6, His13, and His14 are protonated in turn, successively approach the center of mass of folded Aβ monomer, trigger ionic interactions and changes of neighboring turns (Asp7-Ser8, His14-Lys16) and even a distant one (Leu34-Met35), as well as concomitant changes of secondary structure, and promote the conformation transition from unfolded to folded. This observation discloses that protonation can convert these charged residues from originally hydrophilic to "hydrophobic-like". For fibril-like oligomers, the pH susceptibility essentially stems from the pK values of charged residues in the context of the Aβ fibril, and in turn one can predict the dynamic behavior of these residues in the processes of dissociation or stabilization of a fibril by comparing the pK values of residues involved in salt bridges in the normal state with those in the current context. This idea is justified by two fibril models and appears to be applicable to other peptides and their fibril systems.

An Original Monomer Sampling from a Ready‐Made Aβ42 NMR Fibril Suggests a Turn‐β‐Strand Synergetic Seeding Mechanism

“…Residues H6 and Y10 in the parentheses involve the β‐sheet formation intermittently, indicating that the first β‐sheet content formed at disordered region is varying as the simulation evolves. Herein, the salt screening effect may play a similar role to the solution acidity, i. e., lower pH (pH=5.0–5.5) can neutralize the charged residues at disordered region and lead the disordered region to convert into a “hydrophobic” one, as observed by Olubiyi et al′s and our recent simulation . Residues locating at β2 region reach to the RMSD equilibrium at ca 340 ns, and produce another stable β‐sheet content between L34 M35 and V39 V40 (Table S2) linked by turn V36‐G38.…”

“…Herein, the salt screening effect may play a similar role to the solution acidity, i. e., lower pH (pH = 5.0-5.5) can neutralize the charged residues at disordered region and lead the disordered region to convert into a "hydrophobic" one, as observed by Olubiyi et al's [8] and our recent simulation. [50] Residues locating at β2 region reach to the RMSD equilibrium at ca 340 ns, and produce another stable β-sheet content between L34 M35 and V39 V40 (Table S2) linked by turn V36-G38. It reproduces the experimental observation and MD simulation prediction that C-terminus of Aβ42 monomer displays β-strands at residues V39-I41 [51] and exhibits a β-sheet between residues V39-I41 and A30-I32 or between residues V39-I41 and V18-F20.…”

C-Terminal Plays as the Possible Nucleation of the Self-Aggregation of the S-Shape Aβ11–42 Tetramer in Solution: Intensive MD Study

“…32 Secondary structure allocation is in good agreement with the previous studies of the Aβ 1-42 monomer, dimer, and pentamer. 59−61 On the other hand, the S4Aβ 11–42 peptide plays a different role in comparison to the 3Aβ 11-40 oligomer, which forms a richer β-content in the N-terminal. 10 Especially, the hydrophobic domain of the N-terminal (sequence 17–21) of the S4Aβ 11–42 oligomer forms less than 50% of the β-content for each residue in comparison with the corresponding value ∼90% of the U-shape 3Aβ 11-40 peptide.…”

Arginine and Arginine-Rich Peptides as Modulators of Protein Aggregation and Cytotoxicity Associated With Alzheimer’s Disease

“…Amyloid-beta aggregates occur in a variety of assemblies, from low molecular weight oligomers (including dimers, trimers, tetramers, and pentamers) to higher molecular weight oligomers (hexamers, nonamers, dodecamers; Wolff et al, 2017), protofibrils, and fibrils, as well as amorphous aggregates (Jiang et al, 2012). in vitro, the formation of these aggregate species is affected by various factors including the presence and concentration of specific ions, such as metals, as well as pH and temperature (Valerio et al, 2008;Jiang et al, 2012;Bin et al, 2013;Faller et al, 2013;Bhowmik et al, 2014;Zhao and Ai, 2018). Amyloid-beta aggregation is illustrated in Figure 2.…”