Study of aggregate formation of caffeine in water by molecular dynamics simulation

The driving force of assembly formation of caffeine in water has been studied using molecular dynamics (MD) as the tool. A total of 340 ns long MD simulations were conducted with different caffeine concentrations in aqueous solutions. For the study of concentration dependence of aggregate formation all the simulations were performed in isothermal isobaric ensembles, where, pressure was maintained at 1 bar and temperature was kept at 300 K. The thermodynamics of aggregate formation were investigated at 1 bar by varying the temperature from 300 to 325 K. iously developed potential model for caffeine [J. Mol. Struct. THEOCHEM 944 (2010) 116–123] was further validated by comparing solubility limit and also with experimental diffusion coefficients which show excellent agreements. Solvent accessible surface area, radial distribution functions and preferential interaction parameter of caffeine for itself over solvent water clearly indicate the aggregate formation of caffeine in aqueous solutions when the concentration exceeds the solubility limit. It was found that formation of aggregates is driven primarily by the enthalpy of the system. Within the temperature range considered here, aggregate formation shows a quasi equilibrium and the equilibrium constant (hence the standard free energy change) shows a linear relationship to the temperature (ΔG0 (J mol−1) = −3790 + 12.8 × T). Caffeine aggregates show stacking arrangements with considerable overlapping of aromatic rings and a relative orientation of about 98°, which agree very well with the results of NMR studies. ne exhibits a preference for urea over water with a preferential interaction parameter of ∼2. This preferred interaction could be the driving force for dissociation of caffeine aggregates in 8 M urea solution.