Curcumin and kaempferol prevent lysozyme fibril formation by modulating aggregation kinetic parameters

Area of Science:

• Biochemistry
• Biophysics
• Pharmacology

Background:

• Small molecule inhibitors' interaction with protein aggregates is well-studied.
• The modulation of aggregation kinetics by these inhibitors remains poorly understood.

Purpose of the Study:

• Investigate curcumin and kaempferol's ability to control protein aggregation kinetic parameters.
• Understand the mechanism of aggregation inhibition by these potential drug molecules.

Main Methods:

• Utilized thioflavin T fluorescence and static light scattering to study guanidine hydrochloride-induced hen egg white lysozyme aggregation.
• Employed fluorescence quench titration and molecular dynamics simulations with binding free energy calculations to analyze inhibitor-protein interactions.

Main Results:

• Observed contrasting effects of curcumin and kaempferol on aggregation kinetics depending on the measurement probe.
• Both inhibitors were found to extend the nucleation phase of amyloid aggregation.
• Inhibitors bind to the protein's core region, crucial for fibril formation, but do not impact elongation rates post-nucleation.

Conclusions:

• Curcumin and kaempferol inhibit amyloid aggregation by prolonging nucleation.
• Inhibitor binding to the protein core is key to their mechanism.
• This study provides mechanistic insights into aggregation inhibition by small molecules.