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

Dragan B. Ninković, Dušan P. Malenov, Predrag V. Petrović, Edward N. Brothers, Shuqiang Niu, Michael B. Hall, Milivoj R. Belić, Snežana D. Zarić

The role of aromatic and nonaromatic amino acids in amyloid formation was 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. On one hand, in (1) presence of aromatic amino acids contribute significantly 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. On the other hand, stability of amyloids (2), without aromatic residues, is caused by interactions of aliphatic side chains with the backbone and, in some cases, by hydrogen bonds.