Near-Wall Aggregation of Amyloidogenic Aβ 1-40 Peptide: Direct Observation by the FRET

The formation of amyloid fibrils is one of the variants of the self-organization of polypeptide chains. For the amyloid aggregation, the solution must be oversaturated with proteins. The interface of the liquid (solution) and solid (vessel walls) phases can trigger the adsorption of protein molecules, and the resulting oversaturation can initiate conformational transitions in them. In any laboratory experiment, we cannot exclude the presence of surfaces such as the walls of vessels, cuvettes, etc. However, in many works devoted to the study of amyloid formation, this feature is not considered. In our work, we investigated the behavior of the Aβ 1-40 peptide at the water–glass, water–quartz, and water–plastic interface. We carried out a series of simple experiments and showed that the Aβ 1-40 peptide is actively adsorbed on these surfaces, which leads to a significant interaction and aggregation of peptides. This means that the interface can be the place where the first amyloid nucleus appears. We suggest that this effect may also be one of the reasons for the difficulty of reproducing kinetic data when studying the aggregation of the amyloid of the Aβ 1-40 peptide and other amyloidogenic proteins     

Multivariate Prognostic Model for Predicting the Outcome of Critically Ill Patients Using the Aromatic Metabolites Detected by Gas Chromatography-Mass Spectrometry

A number of aromatic metabolites of tyrosine and phenylalanine have been investigated as new perspective markers of infectious complications in the critically ill patients of intensive care units (ICUs). The goal of our research was to build a multivariate model for predicting the outcome of critically ill patients regardless of the main pathology on the day of admission to the ICU. Eight aromatic metabolites were detected in serum using gas chromatography-mass spectrometry. The samples were obtained from the critically ill patients (n = 79), including survivors (n = 44) and non-survivors (n = 35), and healthy volunteers (n = 52). The concentrations of aromatic metabolites were statistically different in the critically ill patients and healthy volunteers. A univariate model for predicting the outcome of the critically ill patients was based on 3-(4-hydroxyphenyl)lactic acid (p-HPhLA). Two multivariate classification models were built based on aromatic metabolites using SIMCA method. The predictive models were compared with the clinical APACHE II scale using ROC analysis. For all of the predictive models the areas under the ROC curve were close to one. The aromatic metabolites (one or a number of them) can be used in clinical practice for the prognosis of the outcome of critically ill patients on the day of admission to the ICU.     

eQE: An open‐source density functional embedding theory code for the condensed phase

In this work, we present the main features and algorithmic details of a novel implementation of the frozen density embedding (FDE) formulation of subsystem density functional theory (DFT) that is specifically designed to enable ab initio molecular dynamics (AIMD) simulations of large‐scale condensed‐phase systems containing 1000s of atoms. This code (available at http://eqe.rutgers.edu ) has been given the moniker of embedded Quantum ESPRESSO (eQE) as it is a generalization of the open‐source Quantum ESPRESSO (QE) suite of programs. The strengths of eQE reside in a hierarchical parallelization scheme that allows for an efficient and fully self‐consistent treatment of the electronic structure (via the addition of an additional DIIS extrapolation layer) while simultaneously exploiting the inherent symmetries and periodicities in the system (via sampling of subsystem‐specific first Brillouin zones and utilization of subsystem‐specific basis sets). While bulk liquids and molecular crystals are two classes of systems that exemplify the utility of the FDE approach (as these systems can be partitioned into weakly interacting subunits), we show that eQE has significantly extended this regime of applicability by outperforming standard semilocal Kohn–Sham DFT (KS‐DFT) for large‐scale heterogeneous catalysts with quite different layer‐specific electronic structure and intrinsic periodicities. eQE features very favorable strong parallel scaling for a model system of bulk liquid water composed of 256 water molecules, which allows for a significant decrease in the overall time to solution when compared to KS‐DFT. We show that eQE achieves speedups greater than one order of magnitude ( ) when performing AIMD simulations of such large‐scale condensed‐phase systems as: (1) molecular liquids via bulk liquid water represented by 1024 independent water molecules (3072 atoms with a 25.3× speedup over KS‐DFT), (2) polypeptide/biomolecule solvation via (gly )₆ solvated in (H₂O)₃₉₅ (1230 atoms with a 38.6× speedup over KS‐DFT), and (3) molecular crystals via a 3 × 3 × 3 periodic supercell of pentacene (1940 atoms with a 12.0× speedup over KS‐DFT). These results represent a significant improvement over the current state‐of‐the‐art and now enable subsystem DFT‐based AIMD simulations of realistically sized condensed‐phase systems of interest throughout chemistry, physics, and materials science.     

Spin densities from subsystem density-functional theory: assessment and application to a photosynthetic reaction center complex model

Subsystem density-functional theory (DFT) is a powerful and efficient alternative to Kohn-Sham DFT for large systems composed of several weakly interacting subunits. Here, we provide a systematic investigation of the spin-density distributions obtained in subsystem DFT calculations for radicals in explicit environments. This includes a small radical in a solvent shell, a π-stacked guanine-thymine radical cation, and a benchmark application to a model for the special pair radical cation, which is a dimer of bacteriochlorophyll pigments, from the photosynthetic reaction center of purple bacteria. We investigate the differences in the spin densities resulting from subsystem DFT and Kohn-Sham DFT calculations. In these comparisons, we focus on the problem of overdelocalization of spin densities due to the self-interaction error in DFT. It is demonstrated that subsystem DFT can reduce this problem, while it still allows to describe spin-polarization effects crossing the boundaries of the subsystems. In practical calculations of spin densities for radicals in a given environment, it may thus be a pragmatic alternative to Kohn-Sham DFT calculations. In our calculation on the special pair radical cation, we show that the coordinating histidine residues reduce the spin-density asymmetry between the two halves of this system, while inclusion of a larger binding pocket model increases this asymmetry. The unidirectional energy transfer in photosynthetic reaction centers is related to the asymmetry introduced by the protein environment.     

Investigating chelating sulfonamides and their use in metalloproteinase inhibitors

Matrix metalloproteinase inhibitors (MMPi) utilize zinc-binding groups (ZBGs) to chelate the catalytic Zn(II) ion resulting in enzyme inhibition. Adapting findings from the literature of Zn(II) ion sensors, we previously reported chelating sulfonamide inhibitors of MMP-2, some of which showed excellent selectivity over other gelatinases (MMP-9). Herein, we greatly expand our investigation of chelating sulfonamides as MMP inhibitors (MMPi) with the synthesis and screening of several new libraries consisting of 2-phenyl-7-sulfonamidobenzimidazole, 2-phenyl-7-sulfonamidobenzoxazole, 7-sulfonamidobenzimidazole, 7-sulfonamidobenzoxazole, and 2-(2-sulfonamidophenyl)-quinoline ZBG derivatives. A novel microwave irradiation synthetic procedure was utilized to rapidly and efficiently prepare these molecules. To better understand the coordination chemistry underlying these ZBGs, crystal structures of representative molecules with several first row transition metals were determined and differences in coordination preferences were considered. Surprisingly, only compounds with the 2-phenyl-7-sulfonamidobenzimidazole ZBG showed inhibition of MMP-2, suggesting that the specific structure of the ZBG can have a pronounced effect of inhibitory activity.     

Current approaches to the synthesis of pyrrolo[2,1-a]isoquinolines (microreview)

Chemistry of Heterocyclic Compounds - This microreview considers methods for the synthesis of pyrrolo[2,1-a]isoquinolines, published from year 2014 until 2018.