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In this paper, we introduce specific approximations to simplify the vibronic treatment in modeling absorption and emission spectra, allowing us to include a huge number of vibronic transitions in the calculations. Implementation of such a simplified vibronic treatment within our general approach for modelling vibronic spectra, based on molecular dynamics simulations and the perturbed matrix method, provided a quantitative reproduction of the absorption and emission spectra of aqueous indole with higher accuracy than the one obtained when using the existing vibronic treatment. Such results, showing the reliability of the approximations employed, indicate that the proposed method can be a very efficient and accurate tool for computational spectroscopy.

Frauds in financial services are an ever-increasing phenomenon, and cybercrime generates multimillion revenues, therefore even a small improvement in fraud detection rates would generate significant savings. This chapter arises from the need to overcome the limitations of the rule-based systems to block potentially fraudulent transactions. After mentioning the limitations of rule-based approach, this chapter explains how machine learning is able to address many of these limitations and, more effectively, identify risky transactions. A novel AI-based fraud detection system – built over a Data Science and Machine Learning – is presented for the pre-processing of transaction data and model training in a batch layer (to periodically retrain the predictive model with new data) while in a stream layer, the real-time fraud detection is handled based on new input transaction data. The architecture presented makes this solution a valuable tool for supporting fraud analysts and for automating the fraud detection processes.

We investigate the coupling between the proton transfer (PT) energetics and the protein-solvent dynamics using the intra-molecular PT in wild type (wt) human carbonic anhydrase II and its ten-fold faster mutant Y7F/N67Q as a test case. We calculate the energy variation upon PT, and from that we also calculate the PT reaction free energy, making use of a hybrid quantum mechanics/molecular dynamics approach. In agreement with the experimental data, we obtain that the reaction free energy is basically the same in the two systems. Yet, we show that the instantaneous PT energy is on average lower in the mutant possibly contributing to the faster PT rate. Analysis of the contribution to the PT energetics of the solvent and of each protein residue, also not in the vicinity of the active site, provides evidence for electrostatic tuning of the PT energy arising from the combined effect of the solvent and the protein environment. These findings open up a way to the more general task of the rational design of mutants with either enhanced or reduced PT rate.

The results of our investigations on the Au-catalyzed regioselective hydration reaction of both alkyl- and aryl-substituted N-propargyl phthalimides directed to the selective formation of the corresponding β-phthalimido ketones are described. Experimental data, in particular the observed regioselectivity, have been qualitatively supported by quantum-chemical calculations carried out on model systems in the framework of Density Functional Theory (DFT) followed by quantum theory of atoms in molecules (QTAIMS). Our results suggest that the electronic features of the initial adduct between the propargyl triple bond and the Au(i) catalyst, in particular the character of the gold-triple bond interaction, are essential for the observed regioselectivity. Other effects, such as the presence of the solvent and the formation of a H-bond between the water molecule and the phthalimido moiety, although apparently irrelevant for the regioselectivity, have proven to be kinetically and catalytically rather important.

The stationary and time-dependent infrared spectrum (IR) of the CO stretching mode (ν

In this work we report a joint experimental and computational study on the 2,5-dimethylfuran oxidation reaction in the gas phase initiated by atomic oxygen O(

Although natural or artificial modified pyrimidine nucleobases represent important molecules with valuable properties as constituents of DNA and RNA, no systematic analyses of the structural aspects of bromo derivatives of cytosine have appeared so far in the literature. In view of the biochemical and pharmaceutical relevance of these compounds, six different crystals containing proton-transfer derivatives of 5-bromocytosine are prepared and analyzed in the solid-state by single crystal X-ray diffraction. All six compounds are organic salts, with proton transfer occurring to the Nimino atom of the pyridine ring. Experimental results are then complemented with Hirshfeld surface analysis to quantitively evaluate the contribution of different intermolecular interactions in the crystal packing. Furthermore, theoretical calculations, based on different arrangements of molecules extracted from the crystal structure determinations, are carried out to analyze the formation mechanism of halogen bonds (XBs) in these compounds and provide insights into the nature and strength of the observed interactions. The results show that the supramolecular architectures of the six molecular salts involve extensive classical intermolecular hydrogen bonds. However, in all but one proton-transfer adducts, weak to moderate XBs are revealed by C–Br…O short contacts between the bromine atom in the fifth position, which acts as XB donor (electron acceptor). Moreover, the lone pair electrons of the oxygen atom of adjacent pyrimidine nucleobases and/or counterions or water molecules, which acts as XB acceptor (electron donor).

Molecular Dynamics simulations in conjunction with principal component analysis have been used to model the processes underlying electrospray (ESI) and ion-mobility mass spectrometry (IMMS) experiments. The triprotonated Bradykinin (BK3+) has been selected as a case study. Our results have shown that the conformational features of solvated BK3+ are essentially maintained during the whole process of droplet evaporation. On the other hand these features result partially lost during the motion of the peptide inside the drift tube where the relative cis-trans stability of the prolyl-peptide bonds turns out to be significantly different from the solution state where all-trans isomers have been systematically found. Collision cross sections (CCS) calculated on the BK3+ gaseous population appear as strongly correlated to the shape of BK3+, in particular its length, which on the other hand is scarcely dependent on the prolyl-peptide bond configuration. This finding suggests that in correspondence of a single IMMS peak, different BK3+ conformers characterized by similar shape can be present. The limitations of a computational modeling at atomistic level of this kind of experiments have been discussed. As a matter of fact our study has only partially reproduced the experimental data: while the position of the peaks, i.e. the values of the calculated CCS, have been reproduced with rather good agreement, the assignment of the various cis–trans conformational states of the prolyl-peptide bond revealed not correct if compared to experimental data. This latter disagreement has been considered to be mainly due to the free energy differences between the various conformational states, resulted rather small and hence not fully captured by the empirical force fields.

In this paper we show how it is possible to treat the quantum vibrational relaxation of a chromophore, embedded in a complex atomic-molecular environment, via the explicit solution of the time-dependent Schroedinger equation once using a proper separation between quantum and semiclassical degrees of freedom. The rigorous theoretical framework derived, based on first principles and making use of well defined approximations/assumptions, is utilized to construct a general model for the kinetics of the vibrational relaxation as obtained by the direct evaluation of the density matrix for all the relevant quantum state transitions. Application to (deuterated) N-methylacetamide (the typical benchmark used as a model for the amino acids) shows that the obtained theoretical-computational approach captures the essential features of the experimental process, unveiling the basic relaxation mechanism involving several vibrational state transitions.

In this work we report a joint experimental and computational study on the 2,5-dimethylfuran oxidation reaction in the gas phase initiated by atomic oxygen O(3P). The experiments have been performed by using vacuum-ultraviolet synchrotron radiation at the Advanced Light Source (ALS) of the Lawrence Berkeley National Laboratory (LBNL), at a temperature of 550 K and a pressure of 8 Torr. The experimental data were supported by quantum-chemical calculations along with a kinetic model, also taking into account the possible involvement of different magnetic states, performed in the framework of the RRKM theory. Propyne, acetaldehyde, methylglyoxal, dimethylglyoxal, 3-penten-2-one, 2,5-dimethylfuran-3(2H)-one, and 1,2-diacetyl ethylene have been identified as the main primary products arising under the conditions of the experiment. Our computational model suggests that these species can be formed at the concentration and branching ratio experimentally observed only in the presence of a non-negligible fraction of non-thermalized intermediates.

The Perturbed Matrix Method is one of the methods to carry out theoretical studies on infrared spectroscopy at a low computational cost. One of the main assumptions adopted up to now is the invariant mode approximation: the actual mass-weighted Hessian eigenvectors of a vibrational center embedded in a chemical environment can be well approximated by the vacuum Hessian eigenvectors with the environment perturbation affecting only the mode frequencies. Herein, we investigate the accuracy of this approximation considering different scenarios. The results demonstrate the accuracy of this approximation providing non-negligible mode coupling only when dealing with extremely intense perturbation fields.

An amphiphilic calix[6]arene, alone or complexed with an axle to form a pseudo-rotaxane, has been embedded into liposomes prepared from 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and the permeability of the membrane-doped liposomes towards Cl− ions has been evaluated by using lucigenin as the fluorescent probe. The pseudo-rotaxane promotes transmembrane transport of Cl− ions more than calix[6]arene does. Surprisingly, the quenching of lucigenin was very fast for liposomes doped with the positively charged axle alone. Molecular dynamics (MD) simulations and quantum-chemical calculations were also carried out for providing a semi-quantitative support to the experimental results.

Correction for ‘Theoretical and experimental study on the O(3P) + 2,5-dimethylfuran reaction in the gas phase’ by Andrea Giustini et al., Phys. Chem. Chem. Phys., 2021, 23, 19424–19434, DOI: 10.1039/D1CP01724A.

The investigation on tandem addition/cyclization reactions of β-(2-aminophenyl)-α,β-ynones with aryl isocyanates/benzoyl isothiocyanate is reported. Experimental results show the suitable conditions to selectively direct the reaction outcome towards the product of 6-exo-dig N-, O-, or S-annulation of the in situ generated alkynyl urea/thiourea intermediate. The reaction of a variety of β-(2-aminophenyl)-α,β-ynones with aryl isocyanates/benzoyl isothiocyanate led to the selective formation of quinazoline or benzoxazine/benzothiazine derivatives, respectively. Density functional theory calculations provide a plausible rationale for the reaction outcome.

Two oxovanadium(IV) complexes containing 4-acyl-5-pyrazolonate-κ2-O,O' bidentate ligands with different chain lengths in the acyl moiety, namely HQC6 (complex I) and HQC17 (complex II), have been synthetized and full characterized, to study their catalytic activity toward the mild and selective oxidation of olefins or model organosulphur substrates, promoted by H2O2 or tert-butyl hydroperoxide (TBHP). The influence due to the type of solvent, likewise ionic liquids (ILs) or conventional medium, was analysed. H2O2 has proven less efficient, in comparison to TBHP. Quantum-chemical calculations have shown that, the key catalytic species involved and, consequently, the actual mechanism might be slightly different according to the oxidant used, i.e. the peroxo VO(QMe)(O2) adduct in the case of H2O2 and the tert-butylperoxo VO(QMe)2(OOt-Bu) adduct in the case of TBHP. Preliminary calculations suggested that, in ionic liquids, the VO(QMe)2 complex might reveal relatively unstable, hence qualitatively explaining the moderate efficiency observed in these media.

Brønsted acids and protic solvents mediate acyl transfer, known as the Mumm rearrangement, from imidates to the corresponding acylamides. This represents a key step in several reactions, for example, the Ugi four-component reaction (U-4CR) and Passerini three-component reaction (P-3CR). Herein, an unprecedented break of the non-reversibility of the Mumm rearrangement is reported. A combination of electrospray tandem mass spectrometry (ESI-MS/MS), infrared multiphoton dissociation (IRMPD) ion spectroscopy and theoretical calculations demonstrates the occurrence of the retro-Mumm rearrangement of protonated isopeptides in the gas phase. In the gas phase, the extra proton acquired during ESI promotes the backward isomerisation reaction in a catalytic fashion.

A series of cis-dioxomolybdenum(VI) α-amino acid containing compounds I–V has been investigated as potential catalyst precursors for the mild and selective oxyfunctionalization of conjugated or unconjugated olefins like styrene, α-methylstyrene, cis-β-methylstyrene, cyclohexene and cyclooctene, using tert-butyl hydroperoxide (TBHP) as main oxidant. All the I–V complexes behaved as active heterogeneous and recyclable catalysts, showing good to quantitative conversion values of the substrate. In all cases, high selectivity toward the corresponding epoxide formation was detected. No substantial difference in terms of efficiency has been observed among the different catalysts I–V, thus confirming that the different nature of the amino acidic side-chain does not strictly affect the catalytic process. Insights into mechanistic details and reaction free energy profile of catalytic oxidations by means of quantum chemical calculations have been discussed.

The Perturbed Matrix Method (PMM) approach to be used in combination with Molecular Dynamics (MD) trajectories (MD-PMM) has been recoded from scratch, improved in several aspects, and implemented in the Gaussian suite of programs for allowing a user-friendly and yet flexible tool to estimate quantum chemistry observables in complex systems in condensed phases. Particular attention has been devoted to a description of rigid and flexible quantum centers together with powerful essential dynamics and clustering approaches. The default implementation is fully black-box and does not require any external action concerning both MD and PMM sections. At the same time, fine-tuning of different parameters and use of external data are allowed in all the steps of the procedure. Two specific systems (Tyrosine and Uridine) have been reinvestigated with the new version of the code in order to validate the implementation, check the performances, and illustrate some new features.

The scientific relevance of quinolines is strictly linked to the fine-tuning of their features by functionalizing the heterocyclic core. Consequently, the compounds of this class are very versatile and can be used as possible drugs for a lot of medical applications. In this work, the inclusion of eight synthetic quinoline derivatives in liposomes formulated with different lipids was investigated in terms of the encapsulation efficiency and to highlight the effect on the liposome size distribution and thermotropic behavior. Excellent encapsulation was accomplished with all the quinoline/phospholipid combinations. Differences in the interactions at the molecular level, dependent on the quinoline molecular scaffolds and lipid structure, were observed, which could significantly bias the interaction with the drug and its release in pharmaceutical applications. Experiments in combination with computational studies demonstrated that the UV absorption of quinolines with expanded conjugation could be affected by the environment polarity. This was probably due to a solvent-dependent ability of these quinolines to stack into aggregates, which could also occur upon inclusion into the lipid bilayer.

Flavoproteins, containing flavin chromophores, are enzymes capable of transferring electrons at very high speeds. The ultrafast photoinduced electron-transfer (ET) kinetics of riboflavin binding protein to the excited riboflavin was studied by femtosecond spectroscopy and found to occur within a few hundred femtoseconds [ Zhong and Zewail, Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 11867-11872 ]. This ultrafast kinetics was attributed to the presence of two aromatic rings that could transfer the electron to riboflavin: the side chains of tryptophan 156 and tyrosine 75. However, the underlying ET mechanism remained unclear. Here, using a hybrid quantum mechanical-molecular dynamics approach, we perform ET dynamics simulations taking into account the motion of the protein and the solvent upon ET. This approach reveals that ET occurs via a major reaction channel involving tyrosine 75 (83%) and a minor one involving tryptophan 156 (17%). We also show that the protein environment is designed to ensure the fast quenching of the riboflavin excited state.

A joint application of experimental and computational approaches has revealed the exceptionally high attitude of crabrolin, a 13-residue peptide with sequence FLPLILRKIVTAL-NH2 , to adopt alpha-helix conformation not only in membrane-mimicking solvents but also in the presence of a not negligible amount of water. Our study shows that this propensity essentially resides in the intrinsic thermodynamic stability of alpha-helix conformation whose kinetic stability is drastically reduced in water solvent. Our analysis suggests that this is due to two effects enhanced by water: a more local effect consisting of the demolition of intra-peptide H-bonds, essential for the alpha-helix formation, and a bulk - electrostatic - effect favoring conformational states more polar than alpha-helix. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

The New Delhi metallo-β-lactamase-1 (NDM-1) enzyme is the most common metallo-β-lactamase identified in many Gram-negative bacteria causing severe nosocomial infections. The aim of this study was to focus the attention on non-active-site residues L209 and Y229 of NDM-1 and to investigate their role in the catalytic mechanism. Specifically, the effect of the Y229W substitution in the L209F variant was evaluated by antimicrobial susceptibility testing, kinetic, and molecular dynamic (MD) studies. The Y229W single mutant and L209F-Y229W double mutant were generated by site-directed mutagenesis. The K(m), k(cat), and k(cat)/K(m) kinetic constants, calculated for the two mutants, were compared with those of (wild-type) NDM-1 and the L209F variant. Compared to the L209F single mutant, the L209F-Y229W double mutant showed a remarkable increase in k(cat) values of 100-, 240-, 250-, and 420-fold for imipenem, meropenem, benzylpenicillin, and cefepime, respectively. In the L209F-Y229W enzyme, we observed a remarkable increase in k(cat)/K(m) of 370-, 140-, and 80-fold for cefepime, meropenem, and cefazolin, respectively. The same behavior was noted using the antimicrobial susceptibility test. MD simulations were carried out on both L209F and L209F-Y229W enzymes complexed with benzylpenicillin, focusing attention on the overall mechanical features and on the differences between the two systems. With respect to the L209F variant, the L209F-Y229W double mutant showed mechanical stabilization of loop 10 and the N-terminal region. In addition, Y229W substitution destabilized both the C-terminal region and the region from residues 149 to 154. The epistatic effect of the Y229W mutation jointly with the stabilization of loop 10 led to a better catalytic efficiency of β-lactams. NDM numbering is used in order to facilitate the comparison with other NDM-1 studies.

The search of antimicrobial peptides (AMP) as candidates for the development of antibiotics is an active research field. In this paper we investigated the role of charged residues in antimicrobial activity by using as a template the previously characterized crabrolin peptide. Mutant peptides in which the charge was diminished (Crabrolin Minus) or increased (Crabrolin Plus) were assayed for their ability to inhibit bacterial growth and to bind model bacterial membranes or lipopolysaccharide (LPS). Structural analysis of both peptides by means of CD, NMR and Molecular Dynamics was also performed and correlated to the biological data. Although native Crabrolin (WT) displays smaller efficacy than other antibacterial peptides with similar length, Crabrolin Plus displays a significant antimicrobial activity while Crabrolin Minus is not active, thus confirming the key role of the positive charge for interacting with the bacterial membrane. Moreover, our results show that charge position has no effect on the helical propensity of the peptides but drastically affects their antimicrobial activity. Antimicrobial activity versus Gram-positive and Gram-negative bacteria, as well as specific interaction with LPS, suggest multiple binding modes for the active peptide.

Two calix[4]resorcinarenes, which differ in the length of the alkyl chain on the methylene bridge between the aromatic rings, have been embedded in unilamellar liposomes prepared from 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine in three host/guest ratios, following two different procedures. The effect of the insertion of the guests has been evaluated through the measurements of the viscosity and the kinetic stability of the liposomal systems by means of the fluorescent probes pyrene and 5(6)-carboxyfluorescein. The presence of the guests reduces the viscosity of the liposomes, suggesting a modification of the bilayer structure. However, this does not affect liposome stability. A calix[4]resorcinarene cavitand with a more rigid conformation compared to the parent resorcinarene, has been also synthetized and embedded in liposomes. The free energy of the insertion of the substrates in the lipid bilayer has been evaluated through Molecular Dynamics simulations.

The theoretical modeling of chemical reactions in condensed phase still represents an open field of investigation for theoretical–computational chemistry. In this context, we have proposed a methodology (the Perturbed Matrix Method [PMM]), based on the first principles of statistical mechanics and on the use of molecular simulations, which has demonstrated its ability in quantitatively predicting the kinetics and the thermodynamics of chemical reactions in complex atomistic environments. In this study, we demonstrate the features of PMM by modeling the resonant Electron Transfer bimolecular reaction between ferrocene and ferrocenium in solution. The obtained results, despite the adopted approximations and the intrinsic limitations of the approach, are in very good agreement with the experimental data and demonstrate the ability of the method for addressing complex reactions in solution and for evaluating the kinetics of slow events out of the potentialities of the state-of-the-art molecular simulations.

The research of new antimicrobial compounds has an impact on public health and economy of many countries. Given the great problem of bacterial resistance, the study of new molecules that bypass this mechanism is of great importance. Trypsin is an enzyme necessary for gut physiology and the peptides it forms could be of great interest to the pharmaceutical industry. In this study the antibacterial activity of undigested and trypsin-hydrolyzed iron-depleted form of lactoferrin, (apo-bLf) and undigested and diferric bovine lactoferrin (bLf) were evaluated against different bacterial species. Apo-bLf was less susceptible to trypsin hydrolysis compared to the diferric form and its tryptic fragments with molecular weight lower than 5000 Da had greater activity than those obtained from the diferric-bLf. It is plausible that the antimicrobial activity is exerted mainly by the interaction of the N-terminal moiety of the protein with the bacterial cell. The in silico analysis of the interdomain movements, showed that the conformation of the active N-terminal part of apo-bLf is more open than that of the diferric form. The increased accessibility of the N-terminal region seems to be responsible for the antimicrobial activity of the apo-bLf and its tryptic fragments.