Investigation on the Mechanisms of Synchronous Interaction of K3Cit with Melamine and Uric Acid That Avoids the Formation of Large Clusters.

Uric acid (UA) has an enormous competence to aggregate over melamine (Mel), producing large UA clusters that "drag" Mel toward them. Such a combination of donor-acceptor pairs provides a robust Mel-UA composite, thereby denoting a high complexity. Thus, a straightforward but pragmatic methodology might indeed require either destruction of the aggregation of UA or impediment of the hydrogen-bonded cluster of Mel and UA. Here, potassium citrate (K3Cit) is used as a potent inhibitor for a significant decrease of large UA-Mel clusters. The underlying mechanisms of synchronous interactions between K3Cit and the Mel-UA pair are examined by the classical molecular dynamics simulation coupled with the enhanced sampling method. K3Cit binds to the Mel-UA pair profoundly to produce a Mel-UA-K3Cit complex with favorable complexation energy (as indicated by the reckoning of pairwise ΔGbind° employing the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method). The strength of interaction follows the order UA-K3Cit > Mel-K3Cit > Mel-UA, thus clearly demonstrating the instability caused by upsetting the π-stacking of UA and hydrogen bonding of Mel-UA simultaneously. The comprehensive, strategically designed "direct approach" and "indirect approach" cluster structure analysis shows that K3Cit reduces the direct approach Mel-UA cluster size significantly irrespective of ensemble variation. Furthermore, the estimation of potentials of mean force (PMFs) reveals that the (UA)decamer-Mel interaction prevails over (UA)tetramer-Mel. The dynamic property (dimer existence autocorrelation functions) proves the essence of dimerization between Mel and UA in the absence and presence of K3Cit. Moreover, the calculation of the preferential interaction parameter provides the concentration at which Mel-K3Cit and UA-K3Cit interactions are predominant over the interaction of Mel and UA.