A stereochemical switch in the aDrs model system, a candidate for a functional amyloid

Area of Science:

• Biochemistry
• Structural Biology
• Materials Science

Background:

• Amyloid fibrils exhibit diverse morphologies linked to varying neurotoxicities, as seen in Alzheimer's disease.
• Amino acid stereochemistry is a key determinant of amyloid deposit architecture.
• Post-translational changes in amino acid chirality may control functional or disease-related amyloid formation.

Purpose of the Study:

• To investigate the impact of stereochemistry on amyloid fibril formation and morphology using anionic dermaseptin (aDrs).
• To explore the role of d-amino acid substitutions in controlling amyloid structure and potential function.
• To assess the influence of stereochemistry on the aggregation kinetics and thermodynamics of aDrs fibrils.

Main Methods:

• Electron microscopy (EM) and Atomic Force Microscopy (AFM) to analyze fibril morphology.
• Enzymatic conversion of anionic dermaseptin (aDrs) to its diastereomer [d-Leu2]-aDrs.
• Molecular dynamics (MD) simulations to study conformational propensities.
• Aggregation experiments using preformed seeds to study superstructural organization.

Main Results:

• Fibril morphology of aDrs isomers is predominantly controlled by the stereochemistry at residue 2.
• Kinetic and thermodynamic parameters of aggregation were minimally affected by stereochemistry.
• Backbone stereochemistry, rather than templating, governed superstructural organization when grown from seeds.
• MD simulations revealed subtle differences in conformational propensities between isomers.

Conclusions:

• d-amino acid substitutions can actively participate in the formation of functional or disease-related amyloid structures.
• Stereochemistry is a critical factor in directing amyloid fibril superstructural organization.
• These findings advance the development of amyloid-based nanomaterials with controlled architectures.