Mechanistic Insight into the Amyloid Fibrillation Inhibition of Hen Egg White Lysozyme by Three Different Bile Acids

Amyloid aggregation of protein is linked to many neurodegenerative diseases. Identification of small molecules capable of targeting amyloidogenic proteins has gained significant importance. Introduction of hydrophobic and hydrogen bonding interactions through site-specific binding of small molecular ligand to protein can effectively modulate the protein aggregation pathway. Here, we investigate the possible roles of three different bile acids, cholic acid (CA), taurocholic acid (TCA), and lithocholic acid (LCA) with varying hydrophobic and hydrogen bonding properties in inhibiting protein fibrillation. Bile acids are an important class of steroid compounds that are synthesized in the liver from cholesterol. Increasing evidence suggests that altered taurine transport, cholesterol metabolism, and bile acid synthesis have strong implications in Alzheimer's disease. We find that the hydrophilic bile acids, CA and TCA (taurine conjugated form of CA), are substantially more efficient inhibitors of lysozyme fibrillation than the most hydrophobic secondary bile acid LCA. Although LCA binds more strongly with the protein and masks the Trp residues more prominently through hydrophobic interactions, the lesser extent of hydrogen bonding interactions at the active site has made LCA a relatively weaker inhibitor of HEWL aggregation than CA and TCA. The introduction of a greater number of hydrogen bonding channels by CA and TCA with several key amino acid residues which are prone to form oligomers and fibrils has weakened the protein's internal hydrogen bonding capabilities for undergoing amyloid aggregation.