Supramolecular citrate poly allylamine hydrochloride nanoparticles for citrate delivery and calcium oxalate nanocrystal dissolution.

HYPOTHESIS: Renal calculi (kidney stones) are mainly made by calcium oxalate and can cause different complications including malfunction of the kidney. The most important urinary stone inhibitors are citrate molecules. Unfortunately, the amount of citrate reaching the kidney after oral ingestion is low. We hypothesized that nanoparticles of polyallylamine hydrochloride (CIT-PAH) carrying citrate ions could simultaneously deliver citrates while PAH would complex oxalate triggering dissolution and removal of CaOx nanocrystals. EXPERIMENTS: We successfully prepared nanoparticles of citrate ions with polyallylamine hydrochloride (CIT-PAH), PAH with oxalate (OX-PAH) and characterize them by Small Angle X ray Scattering (SAXS), Transmission Electron Microscopy (TEM), Dynamic Light Scattering (DLS) and NMR. Dissolution of CaOx nanocrystals in presence of CIT-PAH have been followed with Wide Angle Xray Scattering (WAXS), DLS and Confocal Raman Microscopy. Raman spectroscopy was used to study the dissolution of crystals in synthetic urine samples. The release of citrate from CIT-PAH was followed by diffusion NMR. Molecular dynamics (MD) simulations were carried out to study the interaction of CIT and OX ions with PAH. FINDINGS: CIT-PAH nanoparticles dissolves CaOx nanocrystals as shown by NMR, DLS, TEM and WAXS in water and by Raman spectroscopy in artificial human urine. WAXS and Raman show that the crystal structure of CaOx disappears in the presence of CIT-PAH. DLS shows that the time required for CaOX dissolution will depend on the concentration of CIT-PAH NPs. NMR proves that citrate ions are released from the CIT PAH NPs during CaOX dissolution, MD simulations showed that oxalates exhibit a stronger interaction for PAH than citrate, explaining the removal of oxalate ions and replacement of the citrate in the polymer nanoparticles.

Unveiling the Cleavage Mechanism of an RNA Model Compound on the whole pH Scale: Computations Meet Experiments in the Determination of Reaction Rates.

The knowledge of the mechanism of reactions occurring in solution is a primary research line both in the context of theoretical-computational chemistry and in the field of organic and bio-organic chemistry. Given the importance of the hydrolysis of nucleic acids in life-related phenomena, here we present a combined experimental and computational study on the cleavage of an RNA model compound. This phosphodiester features a cleavage rate strictly dependent on the pH with three different dependence domains. Such experimental evidence, highlighted by an in-depth kinetic investigation, unequivocally suggests a change in the reaction mechanism along the pH scale. In order to interpret the data and to explain the experimental behavior, we have applied a theoretical-computational procedure, involving a hybrid quantum/classical approach, able to model chemical reactions in complex environments, i. e. in solution. This study turns out to quantitatively reproduce the experimental data with accuracy and, in addition, provides useful mechanistic insight into the transesterification process of the investigated compound. The study indicates that the cleavage can occur through an A N D N ${A_N D_N }$ , an A N + D N ${A_N + D_N }$ , and a D N A N ${D_N A_N }$ mechanism depending on the pH values.

A Theoretical-Computational Study of Phosphodiester Bond Cleavage Kinetics as a Function of the Temperature.

The hydrolysis of the phosphodiester bond is an important chemical reaction involved in several biological processes. Here, we study the cleavage of this bond by means of a theoretical-computational method in a model system, the dineopentyl phosphate. By such an approach, we reconstructed the kinetics and related thermodynamics of this chemical reaction along an isochore. In particular, we evaluated the kinetic constants of all the reaction steps within a wide range of temperatures, mostly corresponding to conditions where no experimental measures are available due to the extremely slow kinetics. Our results, in good agreement with the experimental data, show the robustness of our theoretical-computational methodology which can be easily extended to more complex systems.

Modelling Complex Bimolecular Reactions in a Condensed Phase: The Case of Phosphodiester Hydrolysis.

(1) Background: the theoretical modelling of reactions occurring in liquid phase is a research line of primary importance both in theoretical-computational chemistry and in the context of organic and biological chemistry. Here we present the modelling of the kinetics of the hydroxide-promoted hydrolysis of phosphoric diesters. (2) Method: the theoretical-computational procedure involves a hybrid quantum/classical approach based on the perturbed matrix method (PMM) in conjunction with molecular mechanics. (3) Results: the presented study reproduces the experimental data both in the rate constants and in the mechanistic aspects (C-O bond vs. O-P bond reactivity). The study suggests that the basic hydrolysis of phosphodiesters occurs through a concerted ANDN mechanism, with no formation of penta-coordinated species as reaction intermediates. (4) Conclusions: the presented approach, despite the approximations, is potentially applicable to a large number of bimolecular transformations in solution and therefore leads the way to a fast and general method to predict the rate constants and reactivities/selectivities in complex environments.

Rationalizing Sequence and Conformational Effects on the Guanine Oxidation in Different DNA Conformations.

The effect of the environment on the guanine redox potential is studied by means of a theoretical-computational approach. Our data, in agreement with previous experimental findings, clearly show that the presence of consecutive guanine bases in both single- and double-stranded DNA oligomers lowers their reduction potential. Such an effect is even more marked when a G-rich quadruplex is considered, where the oxidized form of guanine is particularly stabilized. To the best of our knowledge, this is the first computational study reporting on a quantitative estimate of the dependence of the guanine redox potential on sequence and conformational effects in complex DNA molecules, ranging from single-stranded DNA to G-quadruplex.