Abstract:
The driving force of assembly formation of caffeine in water and dissociation of these
assembliesin 8 M urea has been studied using molecular dynamics as the tool. All the
simulationshave been conducted in an isothermal isobaric ensemble where, temperature at
298K andpressure at 1 atm. As the first step, a reliable force field for caffeine was developed
andvalidated.The potential model yielded upon fine-tuning force field parameters of caffeine
showed a very good agreement with experimental results such as enthalpy, diffusion
coefficientetc. After the validation, newly developed force field for caffeine was used in all
thesubsequentsimulations.
Twosimulations,one in water and the other in 8 M urea, each containing a ladder of eighteen
caffeinemolecules were run for 4 ns and at the end, their structures were compared.
Comparisonof these structures revealed that formation of assemblies of caffeine in water
whiledisperse of caffeine molecules in 8 M urea. This was evidenced by the variations of
DOPand SAS parameters as a function of simulation time. Interaction energy of caffeinecaffeineindicated that separation of caffeine molecules from each other in 8 M urea while
aggregationof caffeine molecules in aqueous media. Variation of interaction energy of
caffeine-solventin 8 M urea with time showed that favorable binding of urea and water with
caffeinewhile this interaction was higher than the interaction energy of caffeine-water in
watermedium,indicating that entropic influence in the dissociation of caffeine aggregates in
8 M urea. Accumulation of urea around caffeine was clearly seen by the prominent peak in
theRDFof urea and also by the reduction of caffeine diffusion in 8 M urea. The investigation
of numberof hydrogen bonds of caffeine confirmed that interaction of caffeine with urea and
waterislargelymediated through hydrogen bonds.
The association free energy of caffeine indicated that formation of assemblies in water is
energeticallyfavorable. Though dissociation energies are not reflecting the dissociation is
energeticallyfavorable, but the change of entropy in 8 M urea with time indicated that
dissociationof assemblies is mainly governed by the entropy. Also the affinity of urea to bind
with caffeine gives a considerable weight. The dipole moment analysis also indicated that
dimer formation is facilitated by the proper alignment of dipole moment of caffeine
molecules
