Thermodynamics of amyloid fibril formation from chemical depolymerization

Area of Science:

• Biochemistry
• Biophysics
• Structural Biology

Background:

• Amyloid fibrils are protein polymers implicated in diseases and biological processes.
• Their thermodynamic stability, crucial for in vivo processing and lifetime, is less understood than their formation kinetics.

Purpose of the Study:

• To investigate the thermodynamic stability of amyloid fibrils using chemical depolymerization.
• To determine the appropriate polymerization model for amyloid fibril formation and stability.
• To explore the influence of ionic strength on amyloid fibril stability and transition states.

Main Methods:

• Depolymerization of PI3K-SH3 and glucagon amyloid fibrils using chemical denaturants at varying concentrations.
• Analysis of thermodynamic data using cooperative polymerization models.
• Examination of ionic strength dependence of fibril stability and comparison with kinetic data.

Main Results:

• The isodesmic linear polymerization model inadequately describes amyloid fibril depolymerization.
• A cooperative polymerization model quantitatively explains the thermodynamic data.
• Amyloid fibril stability exhibits dependence on ionic strength, consistent with previous kinetic findings.

Conclusions:

• Cooperative polymerization provides a more accurate framework for understanding amyloid fibril thermodynamics.
• The transition state of amyloid fibril growth likely resembles the final product.
• This study enhances our understanding of amyloid fibril stability and formation mechanisms.