Computer Simulation Studies of the Association of Caffeine Molecules in Aqueous Solution and its Role as an Inhibitor on Amyloid Aggregation

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Over the past few years, several studies have proposed the link between caffeine intake and reduced risk of developing Alzheimer’s disease, a neurodegenerative disease. However, the molecular mechanism of the therapeutic potential of caffeine is largely unknown. The entitled thesis seeks to address this issue by means of classical molecular dynamics (MD) simulation. We have carried out classical MD simulation to explore the underlying mechanism of effect of caffeine on aggregation of protein. We started our investigation to explore the self-association of caffeine molecules in presence of NaCl salt, as salt ions are an essential component of living systems. We observed that caffeine molecules self-aggregate by forming clusters by intermolecular π-stacking interaction. Addition of NaCl salt causes the exclusion of water molecules from caffeine hydrophobic surface. An investigation of the effect of temperature on self-association of caffeine molecules in pure water and salt solutions showed that as temperature increases, the probability of formation of higher order clusters decreases. Calculation of potential of mean force and the enthalpic and entropic contribution to it shows that thermodynamics of caffeine association is enthalpy driven in pure water. However, presence of salt leads to entropy driven association specifically at higher temperature. Our analyses point out the transition of thermodynamic behavior of caffeine association to shorter length-scale as the chemical and physical environments are changed. To shed lights on the effect of caffeine on hydrophobic aggregation of biomolecules, we have examined the self-aggregation of hydrophobic di-t-butyl-methane (DTBM) molecules in a regime of caffeine : DTBM stoichiometric ratios. We have observed the disruption of hydrophobic moieties of DTBM aggregates in 10 : 1 or more stochiometric ratio of caffeine : DTBM. We have shown that caffeine aggregates form a hydrophobic environment around a DTBM molecule in which a DTBM molecule is encapsulated, and, these caffeine clusters physically block the other DTBM molecules to interact with the encapsulated DTBM molecule, leading to disruption of DTBM clusters in solutions with 10:1 or higher caffeine to DTBM molecules. Next, we have explored the effect of caffeine on protein aggregation, which is more complex compared to purely hydrophobic assocaition.
Supervisor: Sandip Paul