Molecular Dynamics Simulation Studies of Caffeine Aggregation in Aqueous Solution

Abstract

Molecular dynamics simulations were carried out on a system of eight independent caffeine molecules in a periodic box of water at 300 K, representing a solution near the solubility limit for caffeine at room temperature, using a newly-developed CHARMM-type force field for caffeine in water. Simulations were also conducted for single caffeine molecules in water using two different water models (TIP3P and TIP4P). Water was found to structure in a complex fashion around the planar caffeine molecules, which was not sensitive to the water model used. As expected, extensive aggregation of the caffeine molecules was observed, with the molecules stacking their flat faces against one another like coins, with their methylene groups staggered to avoid steric clashes. A dynamic equilibrum was observed between large n-mers, including stacks with all eight solute molecules, and smaller clusters, with the calculated osmotic coefficient being in acceptable agreement with the experimental value. The insensitivity of the results to water model and the congruence with experimental thermodynamic data suggest that the observed stacking interactions are a realistic representation of the actual association mechanism in aqueous caffeine solutions.

Weakly hydrated surfaces and the binding interactions of small biological solutes

“…It is known from experimental studies that there is extensive aggregation in caffeine solutions and that this aggregation is enthalpically driven (Cesàro et al 1976;Stoesser and Gill 1967). Such an association is indeed found in MD simulations of caffeine solutions (Tavagnacco et al 2011b), as can be seen in a typical ''snapshot'' of a caffeine cluster from these simulations (Fig. 6).…”

“…Because of the significant molecular dipole oriented approximately toward the C-H group at C8 (see Fig. 4), this proton also makes strong interactions with water molecules that are in some ways similar to hydrogen bonds (Tavagnacco et al 2011b), as has been seen in other purines (Teng et al 1988). Note how a band of water density wraps around the ring nitrogen atom, merging at the top and bottom with a small, localized cloud of density directly over the center of the molecule.…”

“…Figure 4 displays the density of water molecule oxygen atoms around the purine caffeine in an aqueous solution (Tavagnacco et al 2011b). This purine, which closely resembles the indole group of tryptophan, is a good subject for such studies because it is somewhat soluble in water, and as a result, experimental thermodynamic data for its solvation are available (Cesàro et al 1976;Stoesser and Gill 1967).…”

“…4 Contours of solvent water density calculated with respect to a reference frame fixed on the center of mass of caffeine, as calculated from a molecular dynamics simulation. The purple surface encloses those regions around the caffeine molecule that on average have a water density 1.3 times higher that the average bulk density (Tavagnacco et al 2011b). The H8 proton, bound to C8, is the one at the 10 o'clock position, the only proton bound to a ring atom and bottom represent water molecules that are hydrophobically hydrating the planar faces.…”

“…The H8 proton, bound to C8, is the one at the 10 o'clock position, the only proton bound to a ring atom and bottom represent water molecules that are hydrophobically hydrating the planar faces. Figure 5 displays the instantaneous position of a few selected water molecules from a single frame of the simulation, superimposed on the density clouds averaged over the entire simulation (Tavagnacco et al 2011b). As can be seen, the water molecules directly over the caffeine faces are oriented so as to point one of their protons directly at the non-hydrogenbonding faces, in principle sacrificing a hydrogen bond to water in the process.…”