Tunability of the CO adsorption energy on a Ni/Cu surface: Site change and coverage effects.

The adsorption energy of carbon monoxide on Ni ad-islands and ultra-thin films grown on the Cu(110) surface can be finely tuned via a complex interplay among diffusion, site change mechanisms, and coverage effects. The observed features of CO desorption can be explained in terms of migration of CO molecules from Cu to Ni islands, competition between bridge and on-top adsorption sites, and repulsive lateral adsorbate-adsorbate interactions. While the CO adsorption energy on clean Cu(110) is of the order of 0.5 eV, Ni-alloying allows for its controlled, continuous tunability in the 0.98-1.15 eV range with Ni coverage. Since CO is a fundamental reactant and intermediate in many heterogeneous catalytic (electro)-conversion reactions, insight into these aspects with atomic level detail provides useful information to potentially drive applicative developments. The tunability range of the CO adsorption energy that we measure is compatible with the already observed tuning of conversion rates by Ni doping of Cu single crystal catalysts for methanol synthesis from a CO2, CO, and H2 stream under ambient pressure conditions.

An evaluation system for postgraduate pediatric residency programs: report of a 3-year experience.

The way a postgraduate medical training program is organized and the capacity of faculty members to function as tutors and to organize effective professional experiences are among the elements that affect the quality of training. An evaluation system designed to target these elements has been implemented within the framework of the Pediatric Residency Program of the University of Padua (Italy). The aim of this report is to describe some aspects of the experience gained in the first 3 years of implementation of the system (2013-2015). Data were collected using four validated questionnaires: the "Resident Assessment Questionnaire", the "Tutor-Assessment Questionnaire", the "Rotation-Assessment Questionnaire", and the "Resident Affairs Committee-Assessment Questionnaire". The response rate was 72% for the "Resident Assessment Questionnaires"; 78% for the "Tutor-/Rotation-Assessment Questionnaires" and 84% for the "Resident Affair Committee-Assessment Questionnaires". The scores collected were validated by psychometric tests. CONCLUSION: The high rates of completed questionnaires returned and the psychometric validation of the results collected indicate that the evaluation system reported herein can be effectively implemented. Efforts should be made to refine this system and, more importantly, to document its impact in improving the Pediatric Residency Program. What is known: • The elements that influence the quality of postgraduate training programs and the knowledge, performance, and competences of residents must be regularly assessed. • Comprehensive evaluation systems for postgraduate residency programs are not universally implemented also because quite often common guidelines and rules, well-equipped infrastructures, and financial resources are missing. What is new: • We show the feasibility of implementing an evaluation system that targets some of the key elements of a postgraduate medical training program in Italy, a European country in which the regulations governing training programs and, notably, the evaluation of residents are still being developed.

Electronic properties of the boroxine-gold interface: evidence of ultra-fast charge delocalization.

We performed a combined experimental and theoretical study of the assembly of phenylboronic acid on the Au(111) surface, which is found to lead to the formation of triphenylboroxines by spontaneous condensation of trimers of molecules. The interface between the boroxine group and the gold surface has been characterized in terms of its electronic properties, revealing the existence of an ultra-fast charge delocalization channel in the proximity of the oxygen atoms of the heterocyclic group. More specifically, the DFT calculations show the presence of an unoccupied electronic state localized on both the oxygen atoms of the adsorbed triphenylboroxine and the gold atoms of the topmost layer. By means of resonant Auger electron spectroscopy, we demonstrate that this interface state represents an ultra-fast charge delocalization channel. Boroxine groups are among the most widely adopted building blocks in the synthesis of covalent organic frameworks on surfaces. Our findings indicate that such systems, typically employed as templates for the growth of organic films, can also act as active interlayers that provide an efficient electronic transport channel bridging the inorganic substrate and organic overlayer.

Validating a set of tools designed to assess the perceived quality of training of pediatric residency programs.

BACKGROUND: The Paediatric Residency Program (PRP) of Padua, Italy, developed a set of questionnaires to assess the quality of the training provided by each faculty member, the quality of the professional experience the residents experienced during the various rotations and the functioning of the Resident Affair Committee (RAC), named respectively: "Tutor Assessment Questionnaire" (TAQ), "Rotation Assessment Questionnaire" (RAQ), and RAC Assessment Questionnaire". The process that brought to their validation are herein presented. METHOD: Between July 2012 and July 2013, 51 residents evaluated 26 tutors through the TAQ, and 25 rotations through the RAQ. Forty-eight residents filled the RAC Assessment Questionnaire. The three questionnaires were validated through a many-facet Rasch measurement analysis. RESULTS: In their final form, the questionnaires produced measures that were valid, reliable, unidimensional, and free from gender biases. TAQ and RAQ distinguished tutors and rotations into 5-6 levels of different quality and effectiveness. The three questionnaires allowed the identification of strengths and weaknesses of tutors, rotations, and RAC. The agreement observed among judges was coherent to the predicted values, suggesting that no particular training is required for developing a shared interpretation of the items. CONCLUSIONS: The work herein presented serves to enrich the armamentarium of tools that resident medical programs can use to monitor their functioning. A larger application of these tools will serve to consolidate and refine further the results presented.

Combined EPR and molecular modeling study of PPI dendrimers interacting with copper ions: effect of generation and maltose decoration.

Understanding the early onset of neurodegeneration is crucial to deploy specific treatments for patients before the process becomes irreversible. Copper has been proposed as a biomarker for many neurodegenerative disorders, being the ion released by pathologically unfolded proteins involved in many biochemical pathways. Dendrimers are macromolecules that bind metal ions with a large ion/ligand ratio, thus, allowing a massive collection of copper. This work provides structural information, obtained via molecular modeling and EPR, for the binding sites of copper in polypropyleneimine (PPI) dendrimers, especially in the maltose decorated form that has potential applications in diagnosis and therapies for various types of neurodegenerations. The analysis of the EPR spectra showed that, at the lowest Cu concentrations, the results are well supported by the calculations. Moreover, EPR analysis at increasing Cu(II) concentration allowed us to follow the saturation behavior of the interacting sites identified by the modeling study.

The interactions of nitrogen dioxide with graphene-stabilized Rh clusters: a DFT study.

We study the interactions of NO2 gas molecules with Rh nanoparticles supported on graphene, using first-principles molecular dynamics in the Car-Parrinello scheme. The stability, morphology, adsorption energies of various models of Rhx nanoparticles (x = 1, 3, 10, 20) supported on graphene, and the binding of NO2 molecules to the Rh clusters, together with its effect on the graphene properties, are reported. Metastable flat structures anchored to the substrate that can bind NO2 to Rh via both N and O atoms are identified, with adsorption energies in the range 60-70 kcal per mole per molecule.

Modeling copper binding to the amyloid-ß peptide at different pH: toward a molecular mechanism for Cu reduction.

Oxidative stress, including the production of reactive oxygen species (ROS), has been reported to be a key event in the etiology of Alzheimer's disease (AD). Cu has been found in high concentrations in amyloid plaques, a hallmark of AD, where it is bound to the main constituent amyloid-ß (Aß) peptide. Whereas it has been proposed that Cu-Aß complexes catalyze the production of ROS via redox-cycling between the Cu(I) and Cu(II) state, the redox chemistry of Cu-Aß and the precise mechanism of redox reactions are still unclear. Because experiments indicate different coordination environments for Cu(II) and Cu(I), it is expected that the electron is not transferred between Cu-Aß and reactants in a straightforward manner but involves structural rearrangement. In this work the structures indicated by experimental data are modeled at the level of modern density-functional theory approximations. Possible pathways for Cu(II) reduction in different coordination sites are investigated by means of first-principles molecular dynamics simulations in the water solvent and at room temperature. The models of the ligand reorganization around Cu allow the proposal of a preferential mechanism for Cu-Aß complex reduction at physiological pH. Models reveal that for efficient reduction the deprotonated amide N in the Ala 2-Glu 3 peptide bond has to be protonated and that interactions in the second coordination sphere make important contributions to the reductive pathway, in particular the interaction between COO(-) and NH(2) groups of Asp 1. The proposed mechanism is an important step forward to a clear understanding of the redox chemistry of Cu-Aß, a difficult task for spectroscopic approaches as the Cu-peptide interactions are weak and dynamical in nature.

Tailoring bimetallic alloy surface properties by kinetic control of self-diffusion processes at the nanoscale.

Achieving control of the nanoscale structure of binary alloys is of paramount importance for the design of novel materials with specific properties, leading to, for example, improved reaction rates and selectivity in catalysis, tailored magnetic behavior in electronics, and controlled growth of nanostructured materials such as graphene. By means of a combined experimental and theoretical approach, we show that the complex self-diffusion mechanisms determining these key properties can be mostly defined by kinetic rather than energetic effects. We explain how in the Ni-Cu system nanoscale control of self-diffusion and segregation processes close to the surface can be achieved by finely tuning the relative concentration of the alloy constituents. This allows tailoring the material functionality and provides a clear explanation of previously observed effects involved, for example, in the growth of graphene films and in the catalytic reduction of carbon dioxide.

The mechanism of hydrogen uptake in [NiFe] hydrogenase: first-principles molecular dynamics investigation of a model compound.

The recent discovery of a model compounds of [NiFe] hydrogenase that catalyzes the heterolytic cleavage of the H(2) molecule into a proton and a stable hydride in water solution under room conditions opened up the possibility to understand the mechanism of H(2) uptake by this peculiar class of enzymes. The simplest model compound belongs to the class of NiRu bimetallic cationic complexes mimicking, in water solution and at room conditions, the hydrogenase active site. By using first-principles molecular dynamics computer simulations, in the Car-Parrinello scheme, we investigated models including the water solvent and nitrate counterions. Several simulations, starting from different initial configurations, provided information on the first step of the H(2) cleavage: (1) the pathway of H(2) approach towards the active site; (2) the role of the ruthenium-bonded water molecule in providing a base that extracts the proton from the activated H(2) molecule; (3) the minor role of Ni in activating the H(2) molecule and its role in stabilizing the hydride produced.

Modeling the Cu+ binding in the 1-16 region of the amyloid-ß peptide involved in Alzheimer's disease.

The coordination of copper to the amyloid-ß (1-16) (Aß) peptide has been investigated because of its relevance for understanding Cu redox activity when the ion is embedded in peptides involved in neurodegenerative diseases. In this work, several reasonable models of Cu(+) coordination were built on the basis of experimental information and investigated by first-principles molecular dynamics simulations in the Car-Parrinello scheme. The propensity of a linear Nδ (His)-Cu-Nδ (His) coordination for Cu(+) is shown by all the models investigated here, with distortions due to weak interactions with the carbonyl O of His 6 and His 13 and with the amide N of His 14. Though the His 6-Cu-His 14 linear coordination is favored in truncated models, the His 13-Cu-His 14 linear coordination is favored by interactions present in the complete solvated and in vacuo models of Cu-Aß (1-16). These interactions include steric hindrance for the expulsion of His 13, hydrogen bonds between Asp and His side chains and a network of electrostatic interactions stabilizing two separated 1-10 and 11-16 peptide regions. The role of linear His 13-Cu-His 14 coordination in stabilizing Cu(I) and in increasing the Cu(II)/Cu(I) reorganization energy can be therefore modulated by boundary conditions acting on the Aß (1-16) ligand.

Modeling of the Zn2+ binding in the 1-16 region of the amyloid beta peptide involved in Alzheimer's disease.

Zinc ions are found at mM concentration in amyloid plaques of Alzheimer's disease and the role of zinc in protein oligomerization is the object of intense investigations. As an in vitro model for studying interactions between Zn(2+) and the Abeta peptide, that is the main component of plaques, the N- and C-termini protected Abeta(1-16) fragment has been chosen because reliable spectroscopic studies in water solution are possible due to the low propensity for oligomerization at pH approximately 6.5, and because all the Zn binding sites of Abeta have been identified in the 1-16 region. In this work we present the results of first principle simulations of several initial models of Zn-Abeta(1-16) complexes. The NMR results about the same system, where His 6, 13, 14 and Glu 11 side-chains coordinate the Zn ion, are strongly supported by these models. Coordination of Asp 1 to Zn drives the complex towards the expulsion of one of initially bonded His side-chains. Coordination of Tyr 10 to Zn is possible only when Tyr 10 is deprotonated. The interplay between physico-chemical properties of the Abeta ligand and the Zn coordination is discussed.

Modeling the interplay of glycine protonation and multiple histidine binding of copper in the prion protein octarepeat subdomains.

The octarepeat region of the prion protein can bind Cu(2+) ions up to full occupancy (one ion per octarepeat) at neutral pH. While crystallographic data show that the HGGG octarepeat subdomain is the basic binding unit, multiple histidine coordination at lower Cu occupancy has been reported by X-ray absorption spectroscopy, EPR, and potentiometric experiments. In this paper we investigate, with first principles Car-Parrinello simulations, the first step for the formation of the Cu low-level binding mode, where four histidine side chains are coordinated to the same Cu(2+) ion. This step involves the further binding of a second histidine to an already HGGG domain bonded Cu(2+) ion. The influence of the pH on the ability of Cu to bind two histidine side chains was taken into account by simulating different protonation states of the amide N atoms of the two glycines lying nearest to the first histidine. Multiple histidine coordination is also seen to occur when glycine deprotonation occurs and the presence of the extra histidine stabilizes the Cu-peptide complex. Though the stabilization effect slightly decreases with the number of deprotonated glycines (reaching a minimum when both N atoms of the two nearest glycines are available as Cu ligands), the system is still capable of binding the second histidine in a 4N tetrahedral (though slightly distorted) coordination, whose energy is very near to that of the crystallographic square-planar 3N1O coordination. This result suggests that at low metal concentration the reorganization energy associated with Cu(II)/Cu(I) reduction is small also at pH approximately 7, when glycines are deprotonated.

Ab initio simulations of Cu binding sites on the N-terminal region of prion protein.

The human prion protein binds Cu2+ ions in the octarepeat domain of the N-terminal tail up to full occupancy at pH 7.4. Recent experiments have shown that the HGGG octarepeat subdomain is responsible for holding the metal bound in a square-planar configuration. By using first principle ab initio molecular dynamics simulations of the Car-Parrinello type, the coordination of copper to the binding sites of the prion protein octarepeat region is investigated. Simulations are carried out for a number of structured binding sites. Results for the complexes Cu(HGGGW)(wat), Cu(HGGG), and [Cu(HGGG)]2 are presented. While the presence of a Trp residue and a water molecule does not seem to affect the nature of the copper coordination, high stability of the bond between copper and the amide nitrogen of deprotonated Gly residues is confirmed in all cases. For the more interesting [Cu(HGGG)]2 complex, a dynamically entangled arrangement of the two domains with exchange of amide nitrogen bonds between the two copper centers emerges, which is consistent with the short Cu-Cu distance observed in experiments at full copper occupancy.

Ab initio molecular dynamics of heme in cytochrome c.

Ab initio molecular dynamics (AIMD) calculations, based on the Car-Parrinello method, have been carried out for three models of heme c that is present in cytochrome c. Both the reduced (Fe(II)) and oxidized (Fe(III)) forms have been analyzed. The simplest models (1R and 1O, respectively) consist of a unsubstituted porphyrin (with no side chains) and two axially coordinated imidazole and ethylmethylthioether ligands. Density functional theory optimizations of these models confirm the basic electronic features and are the starting point for building more complex derivatives. AIMD simulations were performed after reaching the thermal stability at T = 300 K. The evolution of the Fe-L(ax) bond strengths is examined together with the relative rotations of the imidazole and methionine about the axial vector, which appear rather independent from each other. The next models (2R and 2O) contain side chains at the heme to better simulate the actual active site. It is observed that two adjacent propionate groups induce some important effects. The axial Fe-Sdelta bond is only weakened in 2R but is definitely cleaved in the oxidized species 2O. Also the mobility of the Im ligand seems to be reduced by the formation of a strong hydrogen bond that involves the Im Ndelta1-Hdelta1 bond and one carboxylate group. In 2O the interaction becomes so strong that a proton transfer occurs and the propionic acid is formed. Finally, the models 3 include a free N-methyl-acetamide molecule to mimic a portion of the protein backbone. This influences the orientation of carboxylate groups and limits the amount of their hydrogen bonding with the Im ligand. Residual electrostatic interactions are maintained, which are still able to modulate the dissociation of the methionine from the heme.

Molecular statistics of cytochrome c: structural plasticity and molecular environment.

Nuclear magnetic resonance experiments performed on yeast mitochondrial cytochrome c (Cytc), a paradigmatic electron transfer protein, reveal that the two oxidation states have similar structures, but different mobility: despite the few structural differences compared with the reduced form, the oxidized form displays a larger unfolding propensity. Molecular dynamics simulations performed on both NMR reduced and NMR oxidized forms show that the reduced form has a larger solvent-accessible surface area (SASA). Starting from this observation, a molecular statistical approach was then applied in order to correlate the molecular surface to molecular mobility. Simulations started from biased initial conditions corresponding to different molecular sizes were combined with the maximal constrained entropy method. The NMR structure of oxidized Cytc is more suited to expose a smaller SASA than the NMR structure of the reduced form, but the accessible conformational landscape at 300 K around the NMR oxidized structure is flatter than for the NMR reduced structure. Protein configurations of smaller SASA and size display larger plasticity when they resemble the NMR oxidized structure, whereas they are more rigid when they resemble the NMR reduced structure. Implications of the results for the protein properties during its functional process are discussed.

Modeling H3 histone N-terminal tail and linker DNA interactions.

Molecular dynamics computer simulations were performed for the 25-residue N-terminal tail of the H3 histone protein in the proximity of a DNA segment of 10 base pairs (bp), representing a model for the linker DNA in chromatin. Several least biased configurations were used as initial configurations. The secondary structure content of the protein was increased by the presence of DNA close to it, but the locations of the secondary motifs were different for different initial orientations of the DNA grooves with respect to the protein. As a common feature to all simulations, the electrostatic attraction between negatively charged DNA and positively charged protein was screened by the water solvent and counterbalanced by the intrinsic compaction of the protein due to hydrophobic effects. The protein secondary structure limited the covering of DNA by the protein to 4-5 bp. The degree of compaction and charge density of the bound protein suggests a possible role of H3 tail in a nonspecific bending and plasticity of the linker DNA when the protein is located in the crowded dense chromatin.

Hyaluronan chain conformation and dynamics.

An overview of the present state of research in the field of hyaluronan chain conformational aspects is presented. The relationship between structure and dynamics are illustrated for a series of hyaluronan oligomers. Conformational characteristics of hyaluronan chains are discussed, together with the dynamic chain patterns, evaluated by using a theoretical approach to diffusive polymer dynamics. The dependence of correlation times and NMR relaxation parameters from the chain dimension are investigated. Topological features and dimensional properties are related to the structural determinants by using classical computational methods of molecular mechanics and Monte Carlo simulation.