Elucidating the Hydrotropic Mechanism of the Antagonistic Salt PPh4Cl.

PPh4Cl is an antagonistic salt that recently showed promise as a hydrotropic agent. Here, we give mechanistic insights into the PPh4Cl-assisted solubility of a dye molecule using molecular dynamics simulations. Our findings reveal that dye molecules aggregate into a cluster which leads to an accumulation of PPh4+ ions in its vicinity and subsequent exclusion of water molecules from the region. The structural organization is attributed to the preferential interaction of dye molecules and PPh4Cl. The origin of such preference arises from the difference in π-π and CH-π interaction among the pairs. The hydrodynamic radius of PPh4Cl indicates a low propensity for cluster formation, which enhances its hydrotropic behavior. The process of dye dissolution is thermodynamically favored and occurs through a cooperative mechanism. Our studies provide molecular insight into experimental observations crucial for the design of novel hydrotropes with enhanced solubilizing properties.

Appraising the potency of small molecule inhibitors and their graphene surface-mediated organizational attributes on uric acid-melamine clusters.

Uric acid (UA) and melamine (MM) crystallization in humans is associated with adverse medical conditions, including the germination of kidney stones, because of their low solubility. The growth of kidney stones, usually formed on renal papillary facades, is accomplished on the matrix-coated surface by the aggregation of preformed crystals or secondary crystal nucleation. Therefore, the effects of inhibitors such as theobromine (TB) and allopurinol (AP) on MM-UA aggregation are investigated by employing classical molecular dynamics simulations on a graphene surface. This impersonates the exact essence of the precipitation of kidney stones. The interaction between MM-UA is very intense and, thus, large clusters are formed on the surface. The presence of TB and AP will, however, substantially inhibit their aggregation. TB and AP significantly impede UA aggregation in particular. Therefore, lower order UA clusters are formed. These smaller UA clusters then pull a lower number of MM towards themselves, resulting in a smaller order UA-MM cluster. MM and UA aggregation on a 2D graphene surface is found to be spontaneous. There is no difference in these molecules' adsorption with a change in the force field parameters (i.e., GAFF and OPLS-AA) for graphene. Moreover, the greater the surface area of graphene, the more molecules are absorbed. The solute-surface van der Waals interaction energy plays a driving force in the adsorption of solute molecules on the surface. In addition, interactions like hydrogen bonding and π-stacking over the graphene surface involve binding all like molecules. These aggregated solute molecules strongly attract more like molecules until all solute molecules are adsorbed on the graphene surface, as estimated by enhanced sampling. The molecular origin of graphene exfoliation by MM is also described here. The present work helps to design novel kidney stone inhibitors.

Underlying Mechanisms of Allopurinol in Eliminating Renal Toxicity Induced by Melamine-Uric Acid Complex Formation: A Computational Study.

Using molecular dynamics, we address uric acid (UA) replacement by a model small-molecule inhibitor, allopurinol (AP), from its aggregated cluster in a columnar fashion. Experimentally it has been affirmed that AP is efficient in preventing UA-mediated renal stone formation. However, no study has presented the underlying mechanisms yet. Hence, a theoretical approach is presented for mapping the AP, which binds to melamine (MM) and UA clusters. In AP's presence, the higher-order cluster of UA molecules turns into a lower-order cluster, which "drags" fewer MM to them. Consequently, the MM-UA composite structure gets reduced. It is worth noting that UA-AP and AP-MM hydrogen-bonding interactions often play an essential role in reducing the UA-MM cluster size. Interestingly, an AP around UA makes a pillar-like structure, confirmed by defining the point-plane distribution function. The decomposition of the preferential interaction by Kirkwood-Buff integral into different angles like 0°-30°, 30°-60°, and 60°-90° firmly establishes the phenomenon mentioned above. However, the structural order for such π-stacking interactions between AP and UA molecules is not hierarchical but rather more spontaneous. The driving force behind UA-AP-MM composite formation is the favorable complexation energy that can be inferred by computing pairwise binding free energies for all possible combinations. Performing enhanced sampling and quantum calculations further confirms the evidence for UA degradation.

The miscibility and solubility of uric acid and vitamin C in the solution phase and their structural alignment in the solid-liquid interface.

The crystallization of uric acid (UA) in humans is correlated with unpropitious medical predicaments, including gout and kidney stone germination. Its comparatively low solubility in physiological solutions is a significant contributory factor to UA biomineralization. The inhibition of UA aggregation is investigated as a reasonable approach for reducing kidney and gout-related problems. Therefore, we examine the role of vitamin C (Vit-C), a water-soluble vitamin, in the aggregation of UA, and its potency in solubilizing UA has been confirmed experimentally. We notice that Vit-C encapsulates the aggregated UA. Moreover, it can dismantle the assemblies of UA. We have proffered comprehensive molecular mechanisms of the interplay between the aggregated UA and Vit-C. Vit-C molecules are interspersed in solution due to its non-aggregating nature. We perceive that, through hydrogen bonding and aromatic stacking interactions, Vit-C molecules interact with UA molecules. The determination of the Flory-Huggins interaction parameters suggests that the presence of Vit-C enhances the solubility of UA aggregates. In addition, UA molecules are conformed on a monolayer graphene sheet, where they are assembled to create a 2D self-assembly. Vit-C, however, encapsulates and disseminates itself within the aggregated UA molecules on the surface. Therefore, the molecular mechanisms of the impact of Vit-C on UA aggregation can provide relevant insights into drug design against chronic diseases.

Role of Hydrotropes in Sparingly Soluble Drug Solubilization: Insight from a Molecular Dynamics Simulation and Experimental Perspectives.

Drug molecules' therapeutic efficacy depends on their bioavailability and solubility. But more than 70% of the formulated drug molecules show limited effectiveness due to low water solubility. Thus, the water solubility enhancement technique of drug molecules becomes the need of time. One such way is hydrotropy. The solubilizing agent of a hydrophobic molecule is generally referred to as a hydrotrope, and this phenomenon is termed hydrotropy. This method has high industrial demand, as hydrotropes are noninflammable, readily available, environmentally friendly, quickly recovered, cost-effective, and not involved in solid emulsification. The endless importance of hydrotropes in industry (especially in the pharmaceutical industry) motivated us to prepare a feature article with a clear introduction, detailed mechanistic insights into the hydrotropic solubilization of drug molecules, applications in pharma industries, and some future directions of this technique. Thus, we believe that this feature article will become an adequate manual for the pharmaceutical researchers who want to explore all of the past perspectives of the hydrotropic action of hydrotropes in pharmaceutics.

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.

Switching of Self-Assembly to Solvent-Assisted Assembly of Molecular Motor: Unveiling the Mechanisms of Dynamic Control on Solvent Exchange.

Natural biological molecular motors are capable of performing several biological functions, such as fuel production, mobility, transport, and many other dynamic features. Inspired by these biological motors, scientists effectively synthesized artificial molecular motors to mimic several biological functionalities. Several molecular systems, from sensitive materials to molecular motors, are essential for controlling dynamic processes in larger assemblies. In this work, we discuss the self-assembly of molecular motors in water and how this self-assembly switches to the solvent-assisted assembly as solvent changes to a water-THF (tetrahydrofuran) mixture. We present an elaborate description of the morphological changes of molecular motor assemblies from pure water to a water-THF mixture to pure THF. Under the influence of THF solvent, molecular motors form an assembled structure by taking a sufficient number of THF molecules in between themselves, resulting in an assembled molecular motor with a softened core. So, molecular motor assembly swells in the water-THF mixture, and in pure water, it shrinks. This solvent-assisted assembled structure has a specific shape. We have confirmed this assembly as a solvent-assisted assembly with the help of molecular dynamics simulation and quantum chemical analysis. Molecular motor-THF and THF-THF interactions are the main responsible interactions for solvent-assisted assembly over self-assembly. This work is a perfect example of conversion between self-assembly (shrinking) and solvent-assisted assembly (swelling) of molecular motors by adding THF into water or vice versa. A spectacular check on the shrinking and swelling by merely altering solvents illustrates so many intriguing possibilities for an alteration of dynamic processes at the nanoscale.

Inclusion of Theobromine Modifies Uric Acid Aggregation with Possible Changes in Melamine-Uric Acid Clusters Responsible for Kidney Stones.

Theobromine, a naturally occurring substance, can be conceived as a prospective inhibitor for uric acid clustering. In aqueous solution, aggregates of π-stacked uric acid molecules with the larger size of clusters are modified into lower-order clusters with a substantial percentage of monomer by the incorporation of theobromine. The composite made of theobromine-uric acid is expected to have enhanced water solubility, allowing stable kidney stones to be excreted through urine. Interestingly, the strategy for the decomposition with feasible modifications in melamine-uric acid composites (that are hydrogen-bonded) is developed (by implementing the cluster structure analysis technique and binding free energies). The all-atom molecular dynamics (MD) data provides new insights into the structure and dynamics of uric acid along with melamine molecules in the context of aggregation. The simulation in the present study is supported further by structural and dynamical property calculations. The calculations of hydrogen bond dynamics, the average number of hydrogen bonds, dimer existence autocorrelation functions, umbrella sampling, and coordination number theorize that the incorporation of theobromine significantly modifies the aggregated structure of uric acid. The overall complexation energy, along with the quantum chemical calculations, further explains the alternation of aggregated structure. Furthermore, the preferential interaction parameter describes at which concentration theobromine-uric acid interaction (which is π-stacked) predominates over uric acid-uric acid interactions. Interestingly, the interactions between theobromine-melamine and melamine-melamine (which are hydrogen-bonded) are not relevant here. Thus, melamine-uric acid cluster size is reduced owing to the disintegration of self-aggregated uric acid clusters by the involvement of theobromine. Moreover, an excellent agreement is observed between present MD results and experimentally obtained data.

How does temperature modulate the structural properties of aggregated melamine in aqueous solution-An answer from classical molecular dynamics simulation.

In this study, classical molecular dynamics simulation of eight melamine molecules is carried out in water over a temperature range of 300 K to 380 K at an ambient pressure to examine the molecular details of melamine aggregation along with the impact of temperature on the aggregated state of melamine in water. It is found that the hydrogen bonds formed between sp3 N-sp2 N of melamine, which is mainly responsible for the aggregation over the sp3 N-sp3 N, are disturbed mainly by the rise in temperature. These outcomes are complemented by the consideration of an average number of hydrogen bonds per melamine and preferential interaction parameter calculations. The impact of temperature is negligible on the orientational probability between the two triazine cores. The π-π stacking interaction between the two triazine rings plays a less significant role on melamine aggregation. Dynamical calculations, by considering cluster structure analyses and dimer existence autocorrelation function, strengthen the fact of destabilization of aggregated melamine in water with the rise in temperature. With free energy of solvation, association constant along with the binding free energy between a melamine pair gives the thermodynamic point of view of the impact of elevated temperature on melamine aggregation. Interestingly, the potential of mean force calculation using an umbrella sampling technique explains the reasons, in depth, of how do sp3 N-sp2 N interactions confirm the decrease in the initial probability of growth of higher order clusters with the increase in temperature.

Understanding of Structure and Thermodynamics of Melamine Association in Aqueous Solution from a Unified Theoretical and Experimental Approach.

The aggregation propensity of melamine molecules in aqueous solutions in a range of melamine concentrations is investigated by means of a combination of theoretical and experimental approaches. It is observed that the hydrogen bonding interactions of sp3 nitrogen atoms of one melamine with sp2 nitrogen atoms of another melamine play a major role in the melamine association. This finding is complemented by the observed favorable electrostatic energies between melamine molecules. The estimation of the orientational probability of melamine aromatic ring rules out any role of π-π interaction in melamine association. Further, the quantum chemical calculations suggest that a melamine molecule prefers to bind with another like molecule with a dihedral angle ranging from 36° to 46°. We have also determined the dimer existence autocorrelation functions to investigate the melamine-dimer stability with time in aqueous solution. Our results are well validated by the experimental findings (Chapman, R. P.; Averell, P. R.; Harris, R. R. Solubility of Melamine in Water. Ind. Eng. Chem. 1943, 35, 137-138. Ahromi, A. J.; Moosheimer, U. Oxygen Barrier Coatings Based on Supramolecular Assembly of Melamine. Macromolecules 2000, 33, 7582-7587. Yang, C.; Liu. Y. Studying on the Steady-State and Time-Resolved Fluorescence Characteristics of Melamine. Spectrochim. Acta A 2010, 75, 1329-1332. Mircescu, N. E.; Oltean, M.; Chis, V.; Leopold, N. FTIR, FT-Raman, SERS and DFT study on Melamine. Vib. Spectrosc. 2012, 62, 165-171. Makowski. S. J.; Lacher. M.; Schnick. W. Supramolecular Hydrogenbonded Structures between Melamine and N-Heterocycles. J. Mol. Struct. 2012, 1013, 19-25. Li, Z.; Chen, G.; Xu, Y.; Wang, X.; Wang, Z. Study of the Structural and Spectral Characteristics of C3N3(NH2)3(n = 1-4) Clusters. J. Phys. Chem. A 2013, 117, 12511-12518. Li, P.; Arman, D. H.; Wang, H.; Weng, L.; Alfooty, K.; Angawi, R. F.; Chen. B. Solvent Dependent Structures of Melamine: Porous or Non-porous. Cryst. Growth Des. 2015, 15, 1871-1875. Chen, J.; Lei, X.; Peng, B. Study on the Fluorescence Spectra of Melamine in Pure Milk. J. Opt. 2017, 46, 183-186.). Moreover, the thermodynamics of melamine association reveals that the association process is essentially driven by enthalpy, and this enthalpy-driven phenomenon is also confirmed by the experimental isothermal titration calorimetry measurements.