Quantum-Chemistry Study of the Hydrolysis Reaction Profile in Borate Networks: A Benchmark.

This investigation involved an ab initio and Density Functional Theory (DFT) analysis of the hydrolysis mechanism and energetics in a borate network. The focus was on understanding how water molecules interact with and disrupt the borate network, an area where the experimental data are scarce and unreliable. The modeled system consisted of two boron atoms, bridging oxygen atoms, and varying numbers of water molecules. This setup allows for an exploration of hydrolysis under different environmental conditions, including the presence of OH- or H+ ions to simulate basic or acidic environments, respectively. Our investigation utilized both ab initio calculations at the MP2 and CCSD(T) levels and DFT with a range of exchange-correlation functionals. The findings indicate that the borate network is significantly more susceptible to hydrolysis in a basic environment, with respect to an acidic or to a neutral pH setting. The inclusion of explicit water molecules in the calculations can significantly affect the results, depending on the nature of the transition state. In fact, some transition states exhibited closed-ring configurations involving water and the boron-oxygen-boron network; in these cases, there were indeed more water molecules corresponding to lower energy barriers for the reaction, suggesting a crucial role of water in stabilizing the transition states. This study provides valuable insights into the hydrolysis process of borate networks, offering a detailed comparison between different computational approaches. The results demonstrate that the functionals B3LYP, PBE0, and wB97Xd closely approximated the reference MP2 and CCSD(T) calculated reaction pathways, both qualitatively in terms of the mechanism, and quantitatively in terms of the differences in the reaction barriers within the 0.1-0.2 eV interval for the most plausible reaction pathways. In addition, CAM-B3LYP also yielded acceptable results in all cases except for the most complicated pathway. These findings are useful for guiding further computational studies, including those employing machine learning approaches, and experimental investigations requiring accurate reference data for hydrolysis reactions in borate networks.

Evidence of Multiple Crystallization Pathways in Lithium Disilicate: A Metadynamics Investigation.

Metadynamics simulations driven by using two X-ray diffraction peaks identified three alternative crystallization pathways of the lithium disilicate crystal from the melt. The most favorable one passes through the formation of disordered layered structures undergoing internal ordering in a second step. The second pathway involves the formation of phase-separated structures composed of nuclei of ß-cristobalite crystals surrounded by lithium-rich phases in which metasilicate chains are formed. The conversion of these structures to the stable lithium disilicate crystal involves an intermediate structure whose silicate layers are connected by silicate rings with the energy barrier of 2.5 kJ/mol per formula unit (f.u.). The third pathway is highly unlikely because of the huge energy barrier involved (20 kJ/mol per f.u.). This path also involves the passage through a phase-separated structure of an indefinite silica region surrounded mainly by amorphous lithium oxide.

Can DFT Calculations Provide Useful Information for SERS Applications?

Density functional theory (DFT) calculations allow us to reproduce the SERS (surface-enhanced Raman scattering) spectra of molecules adsorbed on nanostructured metal surfaces and extract the most information this spectroscopy is potentially able to provide. The latter point mainly concerns the anchoring mechanism and the bond strength between molecule and metal as well as the structural and electronic modifications of the adsorbed molecule. These findings are of fundamental importance for the application of this spectroscopic technique. This review presents and discusses some SERS-DFT studies carried out in Italy as a collaboration between the universities of Modena and Reggio-Emilia and of Florence, giving an overview of the information that we can extract with a combination of experimental SERS spectra and DFT modeling. In addition, a selection of the most recent studies and advancements on the DFT approach to SERS spectroscopy is reported with commentary.

Alginate Beads Containing Cerium-Doped Mesoporous Glass and Curcumin: Delivery and Stabilization of Therapeutics.

Cancer is a leading cause of death worldwide, its genesis and progression are caused by homeostatic errors, and reactive oxygen species play a major role in promoting aberrant cancer homeostasis. In this scenario, curcumin could be an interesting candidate due to its versatile antioxidant, anti-inflammatory, anti-tumor, anti-HIV, and anti-infection properties. Nonetheless, the major problem related to its use is its poor oral bioavailability, which can be overcome by encapsulating it into small particles, such as hydrogel beads containing mesoporous silica. In this work, various systems have been synthesized: starting from mesoporous silica glasses (MGs), cerium-containing MGs have been produced; then, these systems have been loaded with 4 to 6% of curcumin. Finally, various MGs at different compositions have been included in alginate beads. In vitro studies showed that these hybrid materials enable the stabilization and effective delivery of curcumin and that a synergic effect can be achieved if Ce3+/Ce4+ and curcumin are both part of the beads. From swelling tests, it is possible to confirm a controlled curcumin release compartmentalized into the gastrointestinal tract. For all beads obtained, a curcumin release sufficient to achieve the antioxidant threshold has been reached, and a synergic effect of cerium and curcumin is observed. Moreover, from catalase mimetic activity tests, we confirm the well-known catalytic activity of the couple Ce3+/Ce4+. In addition, an extremely good radical scavenging effect of curcumin has been demonstrated. In conclusion, these systems, able to promote an enzymatic-like activity, can be used as drug delivery systems for curcumin-targeted dosing.

DFT and TD-DFT Study of the Chemical Effect in the SERS Spectra of Piperidine Adsorbed on Silver Colloidal Nanoparticles.

The surface-enhanced Raman scattering (SERS) spectra of piperidine adsorbed on silver/chloride colloids were studied by a combined density functional theory (DFT)/time dependent DFT (TD-DFT) approach. The mechanism of chemical enhancement on the Raman signals is due to at least two contributions: the first comes from the changes in the molecular force constants and the dynamic polarizabilities of the normal modes, when the molecule is chemisorbed. DFT calculations satisfactorily reproduce the SERS spectra of piperidine adsorbed on silver, showing that the species formed on the silver particle is a complex formed by a deprotonated piperidine linked to a silver cation. A second contribution to the SERS chemical enhancement is due to a resonance Raman effect occurring when the wavelength of the Raman excitation falls within the electronic excitation band of the molecule/metal complex. Actually, the SERS spectra of piperidine show a significant dependence on the wavelength of the laser excitation, with a marked enhancement in the green-light region. TD-DFT calculations on the most-probable complex explain this behavior, because a strong excitation band of the complex is calculated in the green spectral region. This pinpoints that a resonance between the exciting radiation and the absorption band of this complex is responsible for this enhancement effect.

Biasing crystallization in fused silica: An assessment of optimal metadynamics parameters.

Metadynamics (MetaD) is a useful technique to study rare events such as crystallization. It has been only recently applied to study nucleation and crystallization in glass-forming liquids such as silicates, but the optimal set of parameters to drive crystallization and obtain converged free energy surfaces is still unexplored. In this work, we systematically investigated the effects of the simulation conditions to efficiently study the thermodynamics and mechanism of crystallization in highly viscous systems. As a prototype system, we used fused silica, which easily crystallizes to ß-cristobalite through MetaD simulations, owing to its simple microstructure. We investigated the influence of the height, width, and bias factor used to define the biasing Gaussian potential, as well as the effects of the temperature and system size on the results. Among these parameters, the bias factor and temperature seem to be most effective in sampling the free energy landscape of melt to crystal transition and reaching convergence more quickly. We also demonstrate that the temperature rescaling from T > Tm is a reliable approach to recover free energy surfaces below Tm, provided that the temperature gap is below 600 K and the configurational space has been properly sampled. Finally, albeit a complete crystallization is hard to achieve with large simulation boxes, these can be reliably and effectively exploited to study the first stages of nucleation.

Computational Insight on the Interaction of Common Blood Proteins with Gold Nanoparticles.

Protein interactions with engineered gold nanoparticles (AuNPs) and the consequent formation of the protein corona are very relevant and poorly understood biological phenomena. The nanoparticle coverage affects protein binding modalities, and the adsorbed protein sites influence interactions with other macromolecules and cells. Here, we studied four common blood proteins, i.e., hemoglobin, serum albumin, α1-antiproteinase, and complement C3, interacting with AuNPs covered by hydrophobic 11-mercapto-1-undecanesulfonate (MUS). We use Molecular Dynamics and the Martini coarse-grained model to gain quantitative insight into the kinetics of the interaction, the physico-chemical characteristics of the binding site, and the nanoparticle adsorption capacity. Results show that proteins bind to MUS-capped AuNPs through strong hydrophobic interactions and that they adapt to the AuNP surfaces to maximize the contact surface, but no dramatic change in the secondary structure of the proteins is observed. We suggest a new method to calculate the maximum adsorption capacity of capped AuNPs based on the effective surface covered by each protein, which better represents the realistic behavior of these systems.

Exploring Translocator Protein (TSPO) Medicinal Chemistry: An Approach for Targeting Radionuclides and Boron Atoms to Mitochondria.

Translocator protein 18 kDa [TSPO or peripheral-type benzodiazepine receptor (PBR)] was identified in the search of binding sites for benzodiazepine anxiolytic drugs in peripheral regions. In these areas, binding sites for TSPO ligands were recognized in steroid-producing tissues. TSPO plays an important role in many cellular functions, and its coding sequence is highly conserved across species. TSPO is located predominantly on the membrane of mitochondria and is overexpressed in several solid cancers. TSPO basal expression in the CNS is low, but it becomes high in neurodegenerative conditions. Thus, TSPO constitutes not only as an outstanding drug target but also as a valuable marker for the diagnosis of a number of diseases. The aim of the present article is to show the lesson we have learned from our activity in TSPO medicinal chemistry and in approaching the targeted delivery to mitochondria by means of TSPO ligands.

Development and Application of a ReaxFF Reactive Force Field for Cerium Oxide/Water Interfaces.

Ceria (CeO2) is a well-known catalytic oxide with many environmental, energy production, and industrial applications, most of them involving water as a reactant, byproduct, solvent, or simple spectator. In this work, we parameterized a Ce/O/H ReaxFF for the study of ceria and ceria/water interfaces. The parameters were fitted to an ab initio training set obtained at the DFT/PBE0 level, including the structures, cohesive energies, and elastic properties of the crystalline phases Ce, CeO2, and Ce2O3; the O-defective structures and energies of vacancy formation on CeO2 bulk and CeO2 (111) surface, as well as the absorption and reaction energies of H2 and H2O molecules on CeO2 (111). The new potential reproduced reasonably well all the fitted properties as well as the relative stabilities of the different ceria surfaces, the oxygen vacancies formation, and the energies and structures of associative and dissociative water molecules on them. Molecular dynamics simulations of the liquid water on the CeO2 (111) and CeO2 (100) surfaces were carried out to study the coverage and the mechanism of water dissociation. After equilibration, on average, 35% of surface sites of CeO2 (111) are hydroxylated whereas 15% of them are saturated with molecular water associatively adsorbed. As for the CeO2 (100) surface, we observed that water preferentially dissociates covering 90% of the available surface sites in excellent agreement with recent experimental findings.

Novel Pet-Degrading Enzymes: Structure-Function from a Computational Perspective.

The bacterium strain Ideonella sakaiensis 201-F6 is able to hydrolyze low-crystallinity PET films at 30 °C due to two enzymes named PETase and MHETase. Since its discovery, many efforts have been dedicated to elucidating the structure and features of those two enzymes, and various authors have highlighted the necessity to optimize both the substrate binding site and the global structure in order to enhance the stability and catalytic activity of these PET biocatalysts so as to make them more suitable for industrial applications. In this review, the strategies adopted by different research groups to investigate the structure and functionality of both PETase and MHETase in depth are described, emphasizing the advantages provided by the use of computational methods to complement and drive experiments. Subsequently, the modifications implemented with protein engineering are discussed. The versatility of the enzymes secreted by I. sakaiensis enables the prediction that they will find several applications in the disposal of PET debris, encouraging a prioritization of efforts in this prolific research field.

Disclosing the Interaction of Gold Nanoparticles with Aß(1-40) Monomers through Replica Exchange Molecular Dynamics Simulations.

Amyloid-ß aggregation is one of the principal causes of amyloidogenic diseases that lead to the loss of neuronal cells and to cognitive impairments. The use of gold nanoparticles treating amyloidogenic diseases is a promising approach, because the chemistry of the gold surface can be tuned in order to have a specific binding, obtaining effective tools to control the aggregation. In this paper, we show, by means of Replica Exchange Solute Tempering Molecular Simulations, how electrostatic interactions drive the absorption of Amyloid-ß monomers onto citrates-capped gold nanoparticles. Importantly, upon binding, amyloid monomers show a reduced propensity in forming ß-sheets secondary structures that are characteristics of mature amyloid fibrils.

Disclosing crystal nucleation mechanism in lithium disilicate glass through molecular dynamics simulations and free-energy calculations.

Unraveling detailed mechanism of crystal nucleation from amorphous materials is challenging for both experimental and theoretical approaches. In this study, we have examined two methods to understand the initial stage of crystal precipitation from lithium disilicate glasses using molecular dynamics simulations. One of the methods is a modified exploring method to find structurally similar crystalline clusters in the glass models, enabling us to find three different embryos, such as Li2Si2O5 (LS2), Li2SiO3 (LS) and Li3PO4 (LP), in the 33Li2O·66SiO2·1P2O5 glass (LS2P1), in which P2O5 is added as a nucleating agent. Interestingly, LS2 and LP crystals were found inside the LS2P1 glass while LS crystal appeared on the glass surface, which agrees with experimental observations. The other method is free energy calculation using a subnano-scale spherical crystal embedded in the glass model. This method, which we called Free-Energy Seeding Method (FESM), allows us to evaluate free energy change as a function of crystal radius and to identify critical size of the crystal precipitation. The free energy profiles for LS and LS2 crystal nuclei in the LS2 glass models possess maximum energy at a critical radius as expected by classical nucleation theory. Furthermore, the critical radius and the energy barrier height agree well with recent experimental investigation, proving the applicability of this method to design glass-ceramics by atomistic modeling.

Computational Insights into the Binding of Monolayer-Capped Gold Nanoparticles onto Amyloid-ß Fibrils.

Amyloids-ß (Aß) fibrils are involved in several neurodegenerative diseases. In this study, atomistic molecular dynamics simulations have been used to investigate how monolayer-protected gold nanoparticles interact with Aß(1-40) and Aß(1-42) fibrils. Our results show that small gold nanoparticles bind with the external side of amyloid-ß fibrils that is involved in the fibrillation process. The binding affinity, studied for both kinds of fibrils as a function of the monolayer composition and the nanoparticle diameter, is modulated by hydrophobic interactions and ligand monolayer conformation. Our findings thus show that monolayer-protected nanoparticles are good candidates to prevent fibril aggregation and secondary nucleation or to deliver drugs to specific fibril regions.

Insights into the Effect of Curcumin and (-)-Epigallocatechin-3-Gallate on the Aggregation of Aß(1-40) Monomers by Means of Molecular Dynamics.

In this study, we compared the effects of two well-known natural compounds on the early step of the fibrillation process of amyloid-ß (1-40), responsible for the formation of plaques in the brains of patients affected by Alzheimer's disease (AD). The use of extensive replica exchange simulations up to the µs scale allowed us to characterize the inhibition activity of (-)-epigallocatechin-3-gallate (EGCG) and curcumin (CUR) on unfolded amyloid fibrils. A reduced number of ß-strands, characteristic of amyloid fibrils, and an increased distance between the amino acids that are responsible for the intra- and interprotein aggregations are observed. The central core region of the amyloid-ß (Aß(1-40)) fibril is found to have a high affinity to EGCG and CUR due to the presence of hydrophobic residues. Lastly, the free binding energy computed using the Poisson Boltzmann Surface Ares suggests that EGCG is more likely to bind to unfolded Aß(1-40) fibrils and that this molecule can be a good candidate to develop new and more effective congeners to treat AD.

Unraveling the complexity of amyloid polymorphism using gold nanoparticles and cryo-EM.

Increasing evidence suggests that amyloid polymorphism gives rise to different strains of amyloids with distinct toxicities and pathology-spreading properties. Validating this hypothesis is challenging due to a lack of tools and methods that allow for the direct characterization of amyloid polymorphism in hydrated and complex biological samples. Here, we report on the development of 11-mercapto-1-undecanesulfonate-coated gold nanoparticles (NPs) that efficiently label the edges of synthetic, recombinant, and native amyloid fibrils derived from different amyloidogenic proteins. We demonstrate that these NPs represent powerful tools for assessing amyloid morphological polymorphism, using cryogenic transmission electron microscopy (cryo-EM). The NPs allowed for the visualization of morphological features that are not directly observed using standard imaging techniques, including transmission electron microscopy with use of the negative stain or cryo-EM imaging. The use of these NPs to label native paired helical filaments (PHFs) from the postmortem brain of a patient with Alzheimer's disease, as well as amyloid fibrils extracted from the heart tissue of a patient suffering from systemic amyloid light-chain amyloidosis, revealed a high degree of homogeneity across the fibrils derived from human tissue in comparison with fibrils aggregated in vitro. These findings are consistent with, and strongly support, the emerging view that the physiologic milieu is a key determinant of amyloid fibril strains. Together, these advances should not only facilitate the profiling and characterization of amyloids for structural studies by cryo-EM, but also pave the way to elucidate the structural basis of amyloid strains and toxicity, and possibly the correlation between the pathological and clinical heterogeneity of amyloid diseases.

Structural origins of the Mixed Alkali Effect in Alkali Aluminosilicate Glasses: Molecular Dynamics Study and its Assessment.

The comprehension of the nonlinear effects provided by mixed alkali effect (MAE) in oxide glasses is useful to optimize glass compositions to achieve specific properties that depend on the mobility of ions, such as the chemical durability, glass transition temperature, viscosity and ionic conductivity. Although molecular dynamics (MD) simulations have already been applied to investigate the MAE on silicates, less effort has been devoted to study such phenomenon in mixed alkali aluminosilicate glasses where alkali cations can act both as modifiers, forming non-bridging oxygens and percolation channels, and as charge compensator of the AlO4- units present in the network. Moreover, the ionic conductivity has not been computed yet; thus, the accuracy of the atomistic simulations in reproducing the MAE on the property is still open to question. In this work, we have validated five major interatomic potentials for the classical MD simulations by modelling the structure, density, glass transition temperature and ionic conductivity for three aluminosilicate glasses, (25 - x)Na2O - x(K2O) - 10(Al2O3) - 65(SiO2) (x = 0, 12.5, 25). It was observed that only the core-shell (CS) polarizable force field well reproduces the experimentally measured MAE on Tg and the ionic conductivity as well as the higher conductivity of single sodium aluminosilicate glass at low temperature and the higher conductivity of single potassium aluminosilicate glass at high temperature. The MAE is related to the suppression of jump events of the alkaline ions between dissimilar sites in the percolation channels consisting of both sodium and potassium ions as in the case of alkaline silicates. The superior reproducibility of the CS potential is originated from the larger and the flexible ring structures due to the smaller Si-O-Si inter-tetrahedra angle, creating appropriate percolation channels for ion conductivity. We also report detailed assessments for using the potential models including the CS potential for investigating MAE on aluminosilicates.

A DFT Approach to the Surface-Enhanced Raman Scattering of 4-Cyanopyridine Adsorbed on Silver Nanoparticles.

A Surface-Enhanced Raman Scattering (SERS) spectrum of 4-cyanopyridine (4CNPy) was recorded on silver plasmonic nanoparticles and analyzed by using Density Functional Theory (DFT) calculations. Two simple molecular models of the metal-4CNPy surface complex with a single silver cation or with a neutral dimer (Ag+-4CNPy, Ag2-4CNPy), linked through the two possible interacting sites of 4CNPy (aromatic nitrogen, N, and nitrile group, CN), were considered. The calculated vibrational wavenumbers and intensities of the adsorbate and the isolated species are compared with the experimental Raman and SERS results. The analysis of the DFT predictions and the experimental data indicates that 4CNPy adsorbs preferentially on neutral/charged active sites of the silver nanoparticles through the nitrogen atom of the aromatic ring with a perpendicular orientation.

DARPin_9-29-Targeted Mini Gold Nanorods Specifically Eliminate HER2-Overexpressing Cancer Cells.

We have demonstrated that designed ankyrin repeat protein (DARPin) _9-29, which specifically targets human epidermal growth factor receptor 2 (HER2), binds tightly to gold mini nanorods (GNRs). Molecular dynamic simulations showed that a single layer of DARPin_9-29 molecules is formed on the surface of the nanorod and that conjugation with the nanorod does not involve the protein's domain responsible for specific binding to HER2. The nanorod-DARPin (DARPin-GNR) conjugate is specifically bound (in nanomolar concentrations) to human breast adenocarcinoma SK-BR-3 cells overexpressing HER2. Illumination by near-infrared light (850 nm) led to almost complete eradication of the conjugate-treated SK-BR-3 cells; the viability of epithelial human breast cancer cells expressing normal amounts of the receptor was much less affected by the illumination. The results reported here pave the way toward application of DARPin-GNR conjugates in phototherapy of cancer.

Multiscale Molecular Dynamics Simulation of Multiple Protein Adsorption on Gold Nanoparticles.

A multiscale molecular dynamics simulation study has been carried out in order to provide in-depth information on the adsorption of hemoglobin, myoglobin, and trypsin over citrate-capped AuNPs of 15 nm diameter. In particular, determinants for single proteins adsorption and simultaneous adsorption of the three types of proteins considered have been studied by Coarse-Grained and Meso-Scale molecular simulations, respectively. The results, discussed in the light of the controversial experimental data reported in the current experimental literature, have provided a detailed description of the (i) recognition process, (ii) number of proteins involved in the early stages of corona formation, (iii) protein competition for AuNP adsorption, (iv) interaction modalities between AuNP and protein binding sites, and (v) protein structural preservation and alteration.

Assessment of Density Functional Approximations for Highly Correlated Oxides: The Case of CeO2 and Ce2O3.

CeO2 based materials are very attractive as catalytic components for industrial processes and environmentally friendly technologies; therefore, a reliable and computationally affordable theoretical description of the main properties of ceria is needed. In particular, the description of the interconversion between the Ce(IV) and Ce(III) oxidation states, on which lies the main chemical features of the cerium oxide, results in quite a challenge at the Density Functional Theory level. Here, we tested several density functional approximations, spanning from GGA to hybrid (Global, Meta-Global, and Range Separated Corrected) functionals, on the structural, vibrational, electronic, and thermochemical properties of bulk CeO2 and Ce2O3. GGA and Meta-GGA xc best predict the thermochemical data, while the discrepancies increase with the introduction of the exact exchange in hybrid functionals. Overall, the Short Range Corrected and Global Hybrid functionals with a percentage of Exact Exchange between 16 and 25 give the best description of the crystal properties. Then, a group of the best performing functionals has been tested on the formation energy of an oxygen vacancy at the (111) CeO2 surface. In general, increasing the amount of exact exchange in the hybrid functionals leads to a better description of the localized Ce 4 f states, while the energy of formation of the O vacancy decreases, worsening compared to the experiment.