Unexpected Importance of Aromatic–Aliphatic and Aliphatic Side Chain–Backbone Interactions in the Stability of Amyloids

Abstract

The role of aromatic and nonaromatic amino acids in amyloid formation has been elucidated by calculating interaction energies between β-sheets in amyloid model systems using density functional theory (B3LYP-D3/6-31G*). The model systems were based on experimental crystal structures of two types of amyloids: (1) with aromatic amino acids, and (2) without aromatic amino acids. Data show that these two types of amyloids have similar interaction energies, supporting experimental findings that aromatic amino acids are not essential for amyloid formation. However, different factors contribute to the stability of these two types of amyloids. In the former, the presence of aromatic amino acids significantly contributes to the strength of interactions between side chains; interactions between aromatic and aliphatic side chains are the strongest, followed by aromatic-aromatic interactions, while aliphatic-aliphatic interactions are the weakest. In the latter, that is, the amyloids without aromatic residues, stability is provided by interactions of aliphatic side chains with the backbone and, in some cases, by hydrogen bonds.

Dual Activity BLEG-1 from Bacillus lehensis G1 Revealed Structural Resemblance to B3 Metallo-β-Lactamase and Glyoxalase II: An Insight into Its Enzyme Promiscuity and Evolutionary Divergence

“…Unlike the phenylalanine residue in YcbL and GloB, Leu-162 did not interact with SLG molecule in BLEG-1, possibly due to their distinct side chain. The bulky aromatic side chain of phenylalanine may impose stronger interactions to SLG molecule than leucine, which has an aliphatic side chain [34]. Additionally, Gln-93 and Phe-97 in the α-helix insert (α3) of YcbL also showed interactions with the Cys-moiety of SLG by hydrophobic interactions and hydrogen bond respectively (Figure 11B).…”

Interactions of Aromatic Residues in Amyloids: A Survey of Protein Data Bank Crystallographic Data

“…Our recent quantum chemical calculations of pairs of amyloid β-sheets indicate that the aromatic–aliphatic interactions contribute the most to amyloid stability, in the case of amyloids with aromatic amino acids, while aliphatic–backbone interactions contribute the most to amyloid stability in the case of aliphatic amyloids (amyloids without aromatic residues). These results also support previous findings that amyloid β-structures can be formed by nonaromatic peptides.…”

Nanostructures Formed by Custom-Made Peptides Based on Amyloid Peptide Sequences and Their Inhibition by 2-Hydroxynaphthoquinone

“…Computational studies have suggested that the presence of glycine and aromatic amino acid residues in the protein sequences readily promote aggregation and/or fibrillation (Gill, 2014 ; Stankovic et al, 2017 ). However, it was found from PDB searches (Ninkovic et al, 2017 ; Stankovic et al, 2017 ) that in the sequences containing only aliphatic residues, e.g., AIIGLM, MVGGVVIA and NKGAII, the interactions between the β sheets of tetramer models were similar in strength to the energies associated with the aromatic residues in the aromatic sequences of KLVFFA and NFGAILS. Both aromatic- aromatic and aliphatic-aliphatic interactions between the tetramers of these aromatic and aliphatic sequences were slated to play an equally important role in amyloid aggregation (Stankovic et al, 2017 ).…”