Side‐chain hydrophobicity and the stability of Aβ_16–22 aggregates

Abstract

Recent mutagenesis studies using the hydrophobic segment of Ab suggest that aromatic p-stacking interactions may not be critical for fibril formation. We have tested this conjecture by probing the effect of Leu, Ile, and Ala mutation of the aromatic Phe residues at positions 19 and 20, on the double-layer hexametric chains of Ab fragment Ab 16-22 using explicit solvent all-atom molecular dynamics. As these simulations rely on the accuracy of the utilized force fields, we first evaluated the dynamic and stability dependence on various force fields of small amyloid aggregates. These initial investigations led us to choose AMBER99SB-ILDN as force field in multiple long molecular dynamics simulations of 100 ns that probe the stability of the wild-type and mutants oligomers. Single-point and double-point mutants confirm that size and hydrophobicity are key for the aggregation and stability of the hydrophobic core region (Ab [16][17][18][19][20][21][22] ). This suggests as a venue for designing Ab aggregation inhibitors the substitution of residues (especially, Phe 19 and 20) in the hydrophobic region (Ab [16][17][18][19][20][21][22] ) with natural and non-natural amino acids of similar size and hydrophobicity.

Self-assembly of the full-length amyloid Aβ42 protein in dimers

“…66,67 Our simulations show a good correlation with experimentally data providing additional support for the use if this field amyloid type proteins. Recently, the ff99IDPs has been developed for IDP monomer simulation and demonstrate the good consistency with NMR data.…”

Oligomerization of FVFLM peptides and their ability to inhibit beta amyloid peptides aggregation: consideration as a possible model

“…It is commonly believed that one of the main driving forces of KLVFFAE (Aβ 16–22 ) organization and stability are electrostatic interactions 55 . Although the prominent role of electrostatic interactions in the anti-parallel ordering of Aβ 16–22 between positively charged C-terminal Lys and negatively charged C-terminal Glu has been pointed out many times 23, 56 , our results that KLVFF peptides can self-assemble (Fig. S2 in SM) suggest that such a popularly accepted proposal falls short of capturing the entire complexity of the process.…”

Stability of Amyloid Oligomers

“…The determination of the "best" force field that agrees with experimental structure is therefore critical for the simulation of performed amyloid fibrils (Berhanu & Hansmann, 2012a). By comparing trajectories of simulations of the performed Aβ 16-22 aggregates that use various common force fields, we found that two recent versions of AMBER force fields have consistently smaller root mean square deviations to the initial configuration than those that rely on one of the other force fields (Berhanu & Hansmann, 2012a). In the simulations that use AMBER force fields, the peptide changes little from the initial conformation exemplifying the stability of the Aβ 16-22 aggregates in simulations with these two force fields.…”

“…Using all-atom molecular dynamics with an explicit solvent (Berhanu & Hansmann, 2012a), we have investigated in a similar effort how L, I, and A mutations of the aromatic F residues at positions 19 and 20 change the stability of the double-layer hexametric chains of Aβ 16À22 preformed fibril aggregates. This stability analysis of single and double point mutants located in the hydrophobic core region of Aβ 16À22 confirms that size and hydrophobicity determine the aggregation process.…”

“…The underlying assumption is that if the model aggregates do not disintegrate during a molecular dynamics run of sufficient length, then the aggregates and proto-fibrils can be considered stable (Berhanu & Hansmann, 2012a). Even though such studies do not involve amyloid assembly, they provide indirect input into the various factors that contribute to or modulate fibril formation.…”