Toward the computer-aided discovery of FabH inhibitors. Do predictive QSAR models ensure high quality virtual screening performance?

Antibiotic resistance has increased over the past two decades. New approaches for the discovery of novel antibacterials are required and innovative strategies will be necessary to identify novel and effective candidates. Related to this problem, the exploration of bacterial targets that remain unexploited by the current antibiotics in clinical use is required. One of such targets is the \(\beta \) -ketoacyl-acyl carrier protein synthase III (FabH). Here, we report a ligand-based modeling methodology for the virtual-screening of large collections of chemical compounds in the search of potential FabH inhibitors. QSAR models are developed for a diverse dataset of 296 FabH inhibitors using an in-house modeling framework. All models showed high fitting, robustness, and generalization capabilities. We further investigated the performance of the developed models in a virtual screening scenario. To carry out this investigation, we implemented a desirability-based algorithm for decoys selection that was shown effective in the selection of high quality decoys sets. Once the QSAR models were validated in the context of a virtual screening experiment their limitations arise. For this reason, we explored the potential of ensemble modeling to overcome the limitations associated to the use of single classifiers. Through a detailed evaluation of the virtual screening performance of ensemble models it was evidenced, for the first time to our knowledge, the benefits of this approach in a virtual screening scenario. From all the obtained results, we could arrive to a significant main conclusion: at least for FabH inhibitors, virtual screening performance is not guaranteed by predictive QSAR models.     

Preferential sites for InAsP/InP quantum wire nucleation using molecular dynamics

In this paper, stress fields at the surface of the capping layer of self-assembled InAsP quantum wires grown on an InP (001) substrate have been determined from atomistic models using molecular dynamics and Stillinger-Weber potentials. To carry out these calculations, the quantum wire compositional distribution was extracted from previous works, where the As and P distributions were determined by electron energy loss spectroscopy and high-resolution aberration-corrected Z-contrast imaging. Preferential sites for the nucleation of wires on the surface of the capping layer were studied and compared with (i) previous simulations using finite element analysis to solve anisotropic elastic theory equations and (ii) experimentally measured locations of stacked wires. Preferential nucleation sites of stacked wires were determined by the maximum stress location at the MD model surface in good agreement with experimental results and those derived from finite element analysis. This indicates that MD simulations based on empirical potentials provide a suitable and flexible tool to study strain dependent atom processes.     

Gauge invariance and spontaneous symmetry breaking in two-gap superconductors

The gauge symmetry of the Ginzburg–Landau theory for two-gap superconductors is analyzed in this letter. We argue that the existence of two different phases, associated with the two independent scalar Higgs fields, explicitly breaks the gauge symmetry of the Ginzburg–Landau Hamiltonian, unless a new additional vector field is included. Furthermore, the interference term, or Josephson coupling, holding a direct dependence with the phase difference, also explicitly breaks down the gauge symmetry. We show that a solution for the problem is achieved by adding an additional kinetic coupling term between the two vector fields, which generates the desired terms through a spontaneous symmetry breaking mechanism. Finally, the electrodynamics of the system is also presented in terms of the supercurrents inside the superconducting region.     

Impact of quantum–classical correspondence on entanglement enhancement by single-mode squeezing

Quantum entanglement between two field modes can be achieved through the collective squeezing of the two respective modes. If single-mode squeezing is performed prior to such a two-mode squeezing, an enhancement of entanglement production can happen. Interestingly, the occurrence of this enhancement can be implicitly linked to the local classical dynamical behavior via the paradigm of quantum–classical correspondence. In particular, the entanglement generated through quantum chaos is found to be hardly enhanced by prior squeezing, since it is bounded by the saturation value of the maximally entangled Schmidt state with fixed energy. These results illustrate that entanglement enhancement via initial squeezing can serve as a useful indicator of quantum chaotic behaviour.     

Effect of magnetic field orientation on fluidized beds of magnetic particles： Theory and experiment

Geldart-A fluidized beds of fine particles experience a jamming transition between a fluid-like state and a solid-like state at a certain superficial gas velocity, that depends on the relative strength of interparticle attractive forces with respect to particle weight, lnterparticle forces provide the bed with a certain tensile strength in the jammed state. In the work presented here we analyze the behavior of a fluidized bed of magnetic particles subjected to an externally applied magnetic field, which contributes to enhance interparticle forces. The importance of the magnetic contribution to interparticle forces is measured by the changes in the tensile strength and the superficial gas velocity at the jamming transition. The link of the field orientation with the microstructure of the bed is discussed,     

Cruciforms' polarized emission confirms disjoint molecular orbitals and excited states

Steady-state and time-resolved polarized spectroscopy studies reveal that electronic excitation to the third excited state of 1,4-distyryl-2,5-bis(arylethynyl)benzene cruciforms results in fluorescence emission that is shifted an angle of ca. 60°. This result is consistent with quantum chemical calculations of the lowest electronic excited states and their transition dipole moments. The shift originates from the disjointed nature of the occupied molecular orbitals being localized on the different branches of the cruciforms.     

Enhanced photochemical [6π] electrocyclization within the lipophilic protein binding site

Photocyclization of N-methyldiphenylamine to N-methylcarbazole is achieved within the microenvironment provided by site I of serum albumins. Quantum yield determinations, combined with transient absorption spectroscopic detection of the dihydrocarbazole intermediate, demonstrate that protein encapsulation provides a subtle control of the kinetic parameters, leading to optimized efficiencies.     

Reactivity of nucleosides with a hydroxyl radical in non-aqueous medium

DNA damage: The reactivity of HO(.) with silylated 2'-deoxyribonucleosides was investigated in acetonitrile by means of a time-resolved technique. The obtained rate constants were in general slightly lower than those reported for the natural nucleosides in water. Analysis of the reaction mixture by UPLC-MS revealed that HO(.) attack occurred at the nucleobase (see scheme).     

A non-damaging method to analyze the configuration and dynamics of nitrotyrosines in proteins

Often, deregulation of protein activity and turnover by tyrosine nitration drives cells toward pathogenesis. Hence, understanding how the nitration of a protein affects both its function and stability is of outstanding interest. Nowadays, most of the in vitro analyses of nitrated proteins rely on chemical treatment of native proteins with an excess of a chemical reagent. One such reagent, peroxynitrite, stands out for its biological relevance. However, given the excess of the nitrating reagent, the resulting in vitro modification could differ from the physiological nitration. Here, we determine unequivocally the configuration of distinct nitrated-tyrosine rings in single-tyrosine mutants of cytochrome?c. We aimed to confirm the nitration position by a non-destructive method. Thus, we have resorted to (1)H-(15)N heteronuclear single quantum coherence(HSQC) spectra to identify the (3)J(N?H) correlation between a (15)N-tagged nitro group and the adjacent aromatic proton. Once the chemical shift of this proton was determined, we compared the (1)H-(13)C HSQC spectra of untreated and nitrated samples. All tyrosines were nitrated at ε positions, in agreement to previous analysis by indirect techniques. Notably, the various nitrotyrosine residues show a different dynamic behaviour that is consistent with molecular dynamics computations.