A possible role for π‐stacking in the self‐assembly of amyloid fibrils

TLDR

Amyloid fibril formation underlies many unrelated diseases, yet its mechanism remains poorly understood, despite the recognized importance of π‑stacking in self‑assembly across chemistry and biochemistry. The authors propose that π‑stacking interactions provide energetic, ordering, and directional contributions to amyloid self‑assembly, offering a new framework for understanding and potentially controlling this process. Analysis of diverse amyloid fragments revealed abundant aromatic residues, suggesting π‑π interactions drive self‑assembly, a hypothesis corroborated by experimental data on amyloid formation and inhibition by short peptide analogs.

Abstract

Amyloid fibril formation is assumed to be the molecular basis for a variety of diseases of unrelated origin. Despite its fundamental clinical importance, the mechanism of amyloid formation is not fully understood. When we analyzed a variety of short functional fragments from unrelated amyloid-forming proteins, a remarkable occurrence of aromatic residues was observed. The finding of aromatic residues in diverse fragments raises the possibility that pi-pi interactions may play a significant role in the molecular recognition and self-assembly processes that lead to amyloid formation. This is in line with the well-known central role of pi-stacking interactions in self-assembly processes in the fields of chemistry and biochemistry. We speculate that the stacking interactions may provide energetic contribution as well as order and directionality in the self-assembly of amyloid structures. Experimental data regarding amyloid formation and inhibition by short peptide analogs also support our hypothesis. The pi-stacking hypothesis suggests a new approach to understanding the self-assembly mechanism that governs amyloid formation and indicates possible ways to control this process.