Computational and experimental studies on β-sheet breakers targeting Aβ1-40 fibrils

Area of Science:

• Biochemistry
• Computational Biology
• Molecular Biology

Background:

• Amyloid-beta 1-40 (Aβ1-40) peptide aggregation is implicated in Alzheimer's disease.
• Beta-sheet breakers are designed to inhibit Aβ1-40 fibril formation.
• Understanding the interaction between Aβ1-40 and beta-sheet breakers is crucial for therapeutic development.

Purpose of the Study:

• To compare the efficacy of three different beta-sheet breakers in inhibiting Aβ1-40 aggregation.
• To investigate the stabilizing effect of beta-sheet breakers on the native alpha-helix structure of Aβ1-40.
• To identify the specific interaction region between Aβ1-40 and the most effective beta-sheet breaker.

Main Methods:

• Extensive molecular dynamics simulations of Aβ1-40 in water with various beta-sheet breakers.
• Experimental validation using Thioflavin T fluorescence, circular dichroism (CD), and mass spectrometry.
• Analysis of beta-sheet breaker structures, including Ac-LPFFD-NH2, Tau-LPFFD-NH2, and Ac-LPFFN-NH2.

Main Results:

• All tested beta-sheet breakers inhibited in vitro fibril formation and prevented beta-sheet folding of Aβ1-40.
• Molecular dynamics simulations and far UV CD showed Ac-LPFFN-NH2 is superior in stabilizing the Aβ1-40 alpha-helix structure.
• Thioflavin T fluorescence confirmed Ac-LPFFN-NH2's higher efficiency in inhibiting Aβ1-40 aggregation.

Conclusions:

• The novel beta-sheet breaker Ac-LPFFN-NH2 demonstrates enhanced efficacy in preventing Aβ1-40 aggregation compared to other variants.
• Ac-LPFFN-NH2 stabilizes the native alpha-helix structure of Aβ1-40, thereby inhibiting its aggregation.
• Mass spectrometry and simulations pinpoint the 17-21 region of Aβ1-40 as the key interaction site for Ac-LPFFN-NH2.