Unraveling diverse action of triton X-100 and methimazole on lysozyme fibrillation/aggregation: Physicochemical insights

Identification of functionalities responsible for prevention of fibrillation in proteins is important to design effective drugs in addressing neurodegenerative diseases. We have used nonionic surfactant triton X-100 (TX-100) and antithyroid drug methimazole (MMI) to understand mechanistic aspects of action of these molecules having different functionalities on hen egg-white lysozyme at different stages of fibrillation. After establishing the nucleation, elongation and maturation stages of fibrillation of protein at 57 degrees C, energetics of interactions with these molecules have been determined by using isothermal titration calorimetry. Differential scanning calorimetry has permitted assessment of thermal stability of the protein at these stages, with or without these molecular entities. The enthalpies of interaction of TX-100 and MMI with protein fibrils suggest importance of hydrogen bonding and polar interactions in their effectiveness towards prevention of fibrils. TX-100, in spite of several polar centres, is unable to prevent fibrillation, rather it promotes. MMI is able to establish polar interactions with interacting strands of the protein and disintegrate fibrils. A rigorous comparison with inhibitors reported in literature highlights importance -OH and >CO functionalities in fibrillation prevention. Even though MMI has hydrogen bonding centres, its efficiency as inhibitor falls after the inhibited lysozyme fibrils further interact and form amorphous aggregates. (C) 2020 Elsevier B.V. All rights reserved.

Automated summary

Identifying the functionalities responsible for preventing protein fibrillation is crucial for developing effective drugs against neurodegenerative diseases. The study investigated the interactions of TX-100 and MMI with lysozyme at different stages of fibrillation, highlighting the importance of hydrogen bonding and polar interactions. A comparison with other inhibitors underscored the significance of -OH and >CO functionalities in preventing fibrillation.