Investigation of the effect of chemical denaturants on hydrophobic interaction of caffeine by molecular dynamics simulation

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