Abstract
Although multiple hydrophobic, aromatic π–π, and electrostatic interactions are proposed to be involved in amyloid fibril formation, the precise interactions within amyloid structures remain poorly understood. Here, we carried out detailed quantum theory of atoms-in-molecules (QTAIM) analysis to examine the hydrophobic core of amyloid parallel and antiparallel β-sheet structures, and found the presence of multiple inter-strand and intra-strand topological neighborhoods, represented by networks of through-space bond paths. Similar bond paths from side chain to side chain and from side chain to main chain were found in a single β-strand and in di- and tripeptides. Some of these bond-path networks were enhanced upon β-sheet formation. Overall, our results indicate that the cumulative network of weak interactions, including various types of hydrogen bonding (X-H—Y; X, Y = H, C, O, N, S), as well as non-H-non-H bond paths, is characteristic of amyloid β-sheet structure. The present study postulated that the presence of multiple through-space bond-paths, which are local and directional, can coincide with the attractive proximity effect in forming peptide assemblies. This is consistent with a new view of the van der Waals (vdW) interactions, one of the origins of hydrophobic interaction, which is updating to be a directional intermolecular force.
Highlights
Amino acids bearing a branched side chain, such as Val, Ile, Thr, and Cys, and aromatic amino acids, such as Tyr, Trp and Phe, have high propensities to form β-strand structure, whereas Ala, Gly and Pro have poor propensities[19,20,21,22]
Bader’s quantum theory of atoms in molecules (QTAIM)[24] is the topological analysis of the molecular electron density based on zero-flux surfaces
This partitioning of electron density by means of the QTAIM is well defined and can be applied to electron-density distributions obtained from both experiment and theory
Summary
Amino acids bearing a branched side chain, such as Val, Ile, Thr, and Cys, and aromatic amino acids, such as Tyr, Trp and Phe, have high propensities to form β-strand structure, whereas Ala, Gly and Pro have poor propensities[19,20,21,22]. We studied through-space weak interactions in the β-strand conformations of the ten short amino acid dipeptides (Ac-X-NHMe, X = Ala, Pro, Leu, Val, Ile, Thr, Cys, Phe, Tyr, and Trp) in terms of bond paths.
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