Innate dynamics and identity crisis of a metal surface unveiled by machine learning of atomic environments

Metals are traditionally considered hard matter. However, it is well known that their atomic lattices may become dynamic and undergo reconfigurations even well below the melting temperature. The innate atomic dynamics of metals is directly related to their bulk and surface properties. Understanding their complex structural dynamics is, thus, important for many applications but is not easy. Here, we report deep-potential molecular dynamics simulations allowing to resolve at an atomic resolution the complex dynamics of various types of copper (Cu) surfaces, used as an example, near the Hüttig (∼1/3 of melting) temperature. The development of deep neural network potential trained on density functional theory calculations provides a dynamically accurate force field that we use to simulate large atomistic models of different Cu surface types. A combination of high-dimensional structural descriptors and unsupervized machine learning allows identifying and tracking all the atomic environments (AEs) emerging in the surfaces at finite temperatures. We can directly observe how AEs that are non-native in a specific (ideal) surface, but that are, instead, typical of other surface types, continuously emerge/disappear in that surface in relevant regimes in dynamic equilibrium with the native ones. Our analyses allow estimating the lifetime of all the AEs populating these Cu surfaces and to reconstruct their dynamic interconversions networks. This reveals the elusive identity of these metal surfaces, which preserve their identity only in part and in part transform into something else under relevant conditions. This also proposes a concept of “statistical identity” for metal surfaces, which is key to understanding their behaviors and properties

Synthesis of amine derivatives from furoin and furil over Ru/Al2O3 catalyst

The direct/reductive amination of carbohydrate-based furoin and furil with NH3/H2 was investigated to access amine derivatives. In the sole presence of NH3, cyclic amines, i.e. 2,3,5,6-tetra(furan-2-yl)pyrazine and 2,2’-bipyridine-3,3’-diol, were generated as main products from furoin and furil, respectively. Over Ru/Al2O3 under NH3/H2, 2-amino-1,2-di(furan-2-yl)ethan-1-ol (i.e. alcohol-amine) was generated as main product with 47% yield at 140 °C for 2 h starting from furoin. The catalyst could be recycled for at least three consecutive runs. An alcohol-imine was the main intermediate that undewent tautomerization to alcohol-enamine/keto-amine leading to cyclic by-products by self-condensation. Supported by DFT calculations, the reactivity of the alcohol-imine intermediate was rationalized by its preferential adsorption on Ru centers via the NH group with the OH group pointing away from the surface, resulting in the formation of alcohol-amine as main product. By combining Ru/Al2O3 and a silica-anchored N-heterocyclic carbene (NHC) catalyst, 2-amino-1,2-di(furan-2-yl)ethan-1-ol could be accessed with 42% overall yield in a single reactor

PARP-inhibitors for BRCA1/2-related advanced HER2-negative breast cancer: A meta-analysis and GRADE recommendations by the Italian Association of Medical Oncology

Background: Approximately 5-10% of unselected breast cancer (BC) patients retain a hereditary predisposition related to a germline mutation in BRCA1/2 genes. The poly-ADP ribose polymerase (PARP)-inhibitors olaparib and talazoparib have been granted marketing authorization by both FDA and EMA for adults with BRCA1/2 germline mutations and HER2-negative (HER2-) advanced BC based on the results from the phase III OlympiAd and EMBRACA trials. Methods: The panel of the Italian Association of Medical Oncology (AIOM) Clinical Practice Guidelines on Breast Cancer addressed two critical clinical questions, adopting the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach and the Evidence to Decision framework (EtD), to develop recommendations on the use of PARP-inhibitors, with respect to single-agent chemotherapy, in patients with BRCA-related triple-negative (clinical question 1) and hormone receptor-positive (HR+)/HER2- (clinical question 2) advanced BC. Results: Two studies were eligible (OlympiAd and EMBRACA). For both clinical questions, the Panel judged the benefit/harm balance probably in favor of the intervention, given the favorable impact in terms of PFS, ORR, and QoL at an acceptable cost in terms of toxicity; the overall certainty of the evidence was low. The panel's final recommendations were conditional in favor of PARP-inhibitors over single-agent chemotherapy in both HR+/HER2-and triple-negative BC. Finally, the Panel identified and discussed areas of uncertainty calling for further exploration. Conclusions: The Panel of AIOM BC Clinical Practice Guideline provided clinical recommendations on the use of PARP-inhibitors, with respect to single-agent chemotherapy, in patients with BRCA-related HER2-advanced BC by adopting the GRADE methodology

Drug delivery mediated by silica based support: does dispersion over H-bond interactions?

Amorphous silica is widely employed in pharmaceutical formulations both as a tableting, anti-caking agent and as a drug delivery system. Particularly, mesoporous silica materials, such as MCM-41, have been recently proposed as efficient supports for the controlled release of drugs. However, little information is known about the interactions between drugs and amorphous silica surfaces, especially at the atomic level. In this work we have applied a computational ab initio approach, exploiting the periodic Density Functional Theory (DFT), to study the adsorption behavior of two popular drugs (aspirin and ibuprofen) on silica surfaces. The CRYSTAL09 1 code was used and PBE level of theory with a triple-\u3b6 polarized basis set was adopted as level of calculus. Two silica surface models were adopted: one with 4.5 OH/nm 2 (hydrophilic character) and the other with 1.5 OH/nm 2 (hydrophobic). These two surface models are representative of two real surfaces treated at low ( 600\ub0C), respectively. Particular importance was given to the study of the role of dispersive interactions (depending on 1/R 6 term) in the adsorption mechanism by including the correction proposed by Grimme 2 . All calculations have revealed that adsorption of the considered drugs on silica surfaces is an exothermic process. In all considered cases dispersion interactions play a crucial role in dictating the features of the drug/silica system, and they are the dominant factor for the highly dehydroxylated surface (see Figure). We have concluded that a subtle balance may exist between specific and directional interactions like H-bonds and non-specific dispersion interactions, with important structural and energetic consequences. From the methodological point of view, this work has shown that pure DFT methods are in serious error when dealing with adsorption processes due to the missing dispersive term. Case A \u2013 without dispersive contributions. Case B \u2013 with dispersive contributions. Figure Ibuprofen in interaction with the 1.5 OH/nm 2 highly dehydroxylated amorphous silica surface. 1 R. Dovesi, R. Orlando, B. Civalleri, C. Roetti, V. R. Saunders, C. M. Zicovich-Wilson, Z. Kristallogr., 2005, 220, 571-573 2 S. Grimme, J. Comput. Chem., 2006, 7(15), 1787-179

Does Dispersion Dominate over H-Bonds in Drug\u2013Surface Interactions? The Case of Silica-Based Materials As Excipients and Drug-Delivery Agents

Amorphous silica is widely employed in pharmaceutical formulations both as a tableting, anticaking agent and as a drug delivery system, whereas MCM-41 mesoporous silica has been recently proposed as an efficient support for the controlled release of drugs. Notwithstanding the relevance of this topic, the atomistic details about the specific interactions between the surfaces of the above materials and drugs and the energetic of adsorption are almost unknown. In this work, we resort to a computational ab initio approach, based on periodic Density Functional Theory (DFT), to study the adsorption behavior of two popular drugs (aspirin and ibuprofen) on two models of an amorphous silica surface characterized by different hydrophilic/hydrophobic properties due to different SiOH surface groups\u2019 density. Particular effort was devoted to understand the role of dispersive (vdW) interactions in the adsorption mechanism and their interplay with H-bond interactions. On the hydrophilic silica surface, the H-bond pattern of the Si\u2013OH groups rearranges to comply with the formation of new H-bond interactions triggered by the adsorbed drug. The interaction energy of ibuprofen with the hydrophilic model of the silica surface is computed to be very close to the sublimation energy of the ibuprofen molecular crystal, accounting for the experimental evidence of ibuprofen crystal amorphization induced by the contact with the mesoporous silica material. For both surface models, dispersion interactions play a crucial role in dictating the features of the drug/silica system, and they become dominant for the hydrophobic surface. It was proved that a competition may exist between directional H-bonds and nonspecific dispersion driven interactions, with important structural and energetic consequences for the adsorption. The results of this work emphasize the inadequacy of plain DFT methods to model adsorption processes involving inorganic surfaces and drugs of moderate size, due to the missing term accounting for London dispersion interactions

Propionic acid derivatives confined in mesoporous silica: monomers or dimers? The case of ibuprofen investigated by static and dynamic ab initio simulations

Confinement in mesoporous silica can greatly increase the solubility of pharmaceutical compounds. Propionic acid derivatives (a very popular class of drugs that include ibuprofen and ketoprofen) would greatly benefit from such technology, given their common apolar character. However, it is still debated whether, after confinement, these drugs are adsorbed on the pore walls as individual molecules or they keep the H-bonded dimeric structure that exists in their crystalline form. Their physical state inside the mesopores could have important consequences on the final performances of the drug delivery system. We employed accurate periodic density functional theory simulations, both static and dynamic, to investigate the issue. We simulated ibuprofen, as a model for all propionic acid derivatives, adsorbed both as a monomer and as a dimer inside a realistic model for the MCM-41 mesoporous silica. We found that adsorption is energetically favored in both cases, driven by both vdW and H-bond interactions. However, through ab initio molecular dynamics, we observed a continuous forming, breaking and reforming of these interactions. In the end, by comparing computed energetics, vibrational spectra and mobility, we were able to provide some important clues on the physical state of this class of drugs inside mesoporous silica, helping to define which drug family (monomer or dimer) is more probable after confinement

Water at hydroxyapatite surfaces: the effect of coverage and surface termination as investigated by all-electron B3LYP-D* simulations

Hydroxyapatite [HA, Ca-10(PO4)(6)(OH)(2)], the main constituent of bones and teeth enamels, is a widely studied and employed biomaterial. Its applications span from dental to orthopedic implants, including bone tissue engineering scaffolds, coating, filler and many others. Previous theoretical and experimental studies have already characterized the physical-chemical foundations of water adsorption on a number of HA surfaces, an essential step in the mechanism of biomaterial integration. Here, we extend such knowledge by simulating, at a hybrid DFT level of theory, different HA surface terminations, both stoichiometric and non-stoichiometric, as free and in interaction with water. Such a goal is achieved at an unprecedented accuracy, with a large all-electron basis set and including dispersion forces contributions. The calculated results are then compared with experimental micro-calorimetric data, showing a good agreement in the loading trend of the (010) surfaces. More generally, this theoretical approach is confirmed to be an efficient tool to analyze these biomaterials, giving the possibility to investigate the HA behavior toward more complex molecules, from amino acids to collagen, at the here-presented level of theory, to shed some light on the complex biomineralization process of human bones and teeth

Models for biomedical interfaces: A computational study of quinone-functionalized amorphous silica surface features

A density functional theory (PBE functional) investigation is carried out, in which a model of an amorphous silica surface is functionalized by ortho- benzoquinone. Surface functionalization with catechol and quinone- based compounds is relevant in biomedical fields, from prosthetic implants to dentistry, to develop multifunctional coatings with antimicrobial properties. The present study provides atomistic information on the specific interactions between the functionalizing agent and the silanol groups at the silica surface. The distinct configurations of the functional groups, the hydrogen bond pattern, the role of dispersion forces and the simulated IR spectra provide detailed insight into the features of this model surface coating. Ab initio molecular dynamics gives further insights into the mobility of the functionalizing groups. As a final step, we studied the condensation reaction with allylamine, via Schiff base formation, to ground subsequent simulations on condensation with model peptides of antimicrobial activity