Conformational Variability of Amyloid-β and the Morphological Diversity of Its Aggregates

Protein folding is the most fundamental and universal example of biomolecular self-organization and is characterized as an intramolecular process. In contrast, amyloidogenic proteins can interact with one another, leading to protein aggregation. The energy landscape of amyloid fibril formation is characterized by many minima for different competing low-energy structures and, therefore, is much more enigmatic than that of multiple folding pathways. Thus, to understand the entire energy landscape of protein aggregation, it is important to elucidate the full picture of conformational changes and polymorphisms of amyloidogenic proteins. This review provides an overview of the conformational diversity of amyloid-beta (A beta) characterized from experimental and theoretical approaches. A beta exhibits a high degree of conformational variability upon transiently interacting with various binding molecules in an unstructured conformation in a solution, forming an alpha-helical intermediate conformation on the membrane and undergoing a structural transition to the beta-conformation of amyloid fibrils. This review also outlines the structural polymorphism of A beta amyloid fibrils depending on environmental factors. A comprehensive understanding of the energy landscape of amyloid formation considering various environmental factors will promote drug discovery and therapeutic strategies by controlling the fibril formation pathway and targeting the consequent morphology of aggregated structures.

Automated summary

Protein folding and protein aggregation are important examples of biomolecular self-organization. Understanding the conformational changes and polymorphisms of amyloidogenic proteins, as well as the influence of environmental factors on amyloid fibrils, is crucial for understanding the energy landscape of protein aggregation and for drug discovery and therapeutic strategies.