Understanding the role of temperature change and the presence of NaCl salts on caffeine aggregation in aqueous solution: from structural and thermodynamics point of view.

To examine the molecular level understanding of temperature induced self-association of caffeine molecules in aqueous solution both in the presence and absence of salt NaCl, we have performed long MD simulations at a regime of temperatures ranging from 275 to 350 K with a temperature difference of 25 K. The calculations of different site-site radial distribution functions followed by coordination number analyses, the calculations of preferential interaction parameters, solvent accessible surface area, and cluster structure analyses show a depletion in the caffeine association propensity with increasing temperature. We have also observed the salting out effect of caffeine molecules in salt solution. The simultaneous presence of polar and nonpolar groups in a caffeine molecule leads to anisotropic hydration. Specifically, the hydration tendency of caffeine hydrophobic sites increases with increasing temperature, while hydrophilic sites tend to be less hydrated. This leads to a decrease in caffeine association. In accordance with some experimental studies on thermodynamics of caffeine association, we have also observed enthalpy driven association in pure water. But the presence of salt leads to entropy driven association specifically at higher temperature. This is due to the relatively stronger interactions of salt ions with caffeine at higher temperature.