Caffeine Inhibits Tau Aggregation and Destabilizes the Fibril Associated with Chronic Traumatic Encephalopathy: A REST2 and Conventional MD Simulations Study

Chronic traumatic encephalopathy (CTE) is a unique tauopathy mostly diagnosed in contact sports athletes, such as those active in American football, boxing, soccer, etc. The hyperphosphorylated fibrillar aggregates composed of self-assembled tau protein are the pathological hallmark of CTE, and inhibiting the aggregation or disassociating the fibrillar aggregates has been considered a promising avenue to prevent or treat CTE. Caffeine (CA) is a well-known psychostimulant and can be found in coffee, tea, and soft drinks. In vitro experiments revealed that CA could effectively inhibit wild-type tau aggregation and disassemble preformed fibrils. However, the atomic effect and the underlying molecular mechanisms remain largely elusive. In this study, we performed a multitude of replica exchange with solute tempering 2 (REST2) and conventional molecular dynamics (CMD) simulations of 43.8 μs in total on tau models with and without CA, including the third and fourth microtubule-binding repeats (R3-R4) tau monomer and CTE-related R3-R4 tau protofibril and fibril. The results revealed that CA could prominently inhibit the β-sheet formation of the monomer and disrupt the β-sheet structure of the protofibril, inducing the monomer and protofibril to adopt loosely packed or extended conformations. H-bonding and π–π stacking interactions drove the binding of CA on the monomer, while hydrophobic interactions made an extra contribution to the binding of CA on the protofibril. Strikingly, CA could stably bind to the hydrophobic cavity of the protofibril, which might occupy the space and prevent the entering of the aggregation cofactor. What is more, CA destabilized the fibril and played a role in reversing the liquid-to-solid phase transition (LSPT) of tau. Our study systematically uncovered the atomic-level effect of CA on tau aggregation, which offers a theoretical foundation for the design of drugs to prevent or treat CTE.