Combining structural proteomics experimental data with computational methods is a powerful tool for protein structure prediction. Here, we apply a recently-developed approach for de novo protein ...structure determination based on the incorporation of short-distance crosslinking data as constraints in discrete molecular dynamics simulations (CL-DMD) for the determination of conformational ensemble of the intrinsically disordered protein α-synuclein in the solution. The predicted structures were in agreement with hydrogen-deuterium exchange, circular dichroism, surface modification, and long-distance crosslinking data. We found that α-synuclein is present in solution as an ensemble of rather compact globular conformations with distinct topology and inter-residue contacts, which is well-represented by movements of the large loops and formation of few transient secondary structure elements. Non-amyloid component and C-terminal regions were consistently found to contain β-structure elements and hairpins.
The 2.MED1 phylogenetic branch of Yersinia pestis of the medieval biovar became widespread in the Caspian Sea region, the Caucasus, and the Northern Aral Sea region in the 20th century, causing ...outbreaks and epizootics of plague there. Some of the formed natural foci of 2.MED1 still show epizootic activity and retain their epidemic potential. In this work, we carried out a phylogenetic analysis of 46 Y. pestis strains of the medieval biovar isolated in the Caucasus, the Caspian Sea, and the Northern Aral Sea regions during epidemic outbreaks and epizootics from 1922-2014. The obtained phylogenetic data, together with epidemiological and epizootological data accumulated over a period of about a hundred years, indicate the presence of two waves of penetration of the 2.MED1 branch into the Caucasus. The first occurred, apparently, in the first half of the 20th century as a result of the penetration of 2.MED1 from the foci of the Northern and North-Western Caspian Sea. The second wave was caused by the spread of 2.MED1 from the Northern Aral to the foci of the North-Western, Northern and Eastern Caspian Sea regions at the beginning of the second half of the 20th century, followed by introduction into the Pre-Caucasus and Transcaucasia. The rapid spread of 2.MED1 could be associated with the transfer of the pathogen by land and sea transport in the process of economic activity of the population.
The use of highly toxic rocket fuel based on 1,1-dimethylhydrazine (UDMH) in many types of carrier rockets poses a threat to environment and human health associated with an ingress of UDMH into ...wastewater and natural reservoirs and its transformation with the formation of numerous toxic nitrogen-containing products. Their GC-MS quantification in aqueous samples requires matrix change and is challenging due to high polarity of analytes. To overcome this problem, accelerated water sample preparation (AWASP) based on the complete removal of water with anhydrous sodium sulfate and transferring analytes into dichloromethane was used. Twenty-nine UDMH transformation products including both the acyclic and heterocyclic compounds of various classes were chosen as target analytes. AWASP ensured attaining near quantitative extraction of 23 compounds with sample preparation procedure duration of no more than 5 min. Combination of AWASP with gas chromatography–mass spectrometry and using pyridine-d5 as an internal standard allowed for developing the rapid, simple, and low-cost method for simultaneous quantification of UDMH transformation products with detection limits of 1–5 μg L−1 and linear concentration range covering 4 orders of magnitude. The method has been validated and successfully tested in the analysis of aqueous solutions of rocket fuel subjected to oxidation with atmospheric oxygen, as well as pyrolytic gasification in supercritical water modelling wastewater from carrier rockets launch sites.
One of the most promising applications of ionic liquids (ILs) with 1-butyl-3-methylimidazolium (bmim) cation is based on their unique ability to dissolve and fractionate lignocellulosic biomass, ...allowing for the development of green biorefining technologies. A complete dissolution of lignocellulose requires prolonged treatment at elevated temperatures, which can cause the partial degradation of ILs. In the present study, a combination of various analytical techniques (GC-MS, HPLC-HRMS, 2D-NMR, synchronous thermal analysis) was used for the comprehensive characterization of bmim acetate, chloride, and methyl sulfate degradation products formed at 150 °C during 6- and 24-h thermal treatment. A number of volatile and non-volatile products, including monomeric and dimeric alkyl substituted imidazoles, alcohols, alkyl amines, methyl and butyl acetates, and N-alkylamides, was identified. By thermal lability, ILs can be arranged in the following sequence, coinciding with the decrease in basicity of the anion: bmimOAc > bmimCl > bmimMeSO4. The accumulation of thermal degradation products in ILs, in turn, affects their physico-chemical properties and thermal stability, and leads to a decrease in the decomposition temperature, a change in the shape of the thermogravimetric curves, and the formation of carbon residue during pyrolysis.
Combining structural proteomics experimental data with computational methods is a powerful tool for protein structure prediction. Here, we apply a recently developed approach for de novo protein ...structure determination based on the incorporation of short-distance crosslinking data as constraints in discrete molecular dynamics simulations (CL-DMD), for the determination of the conformational ensemble of tau protein in solution. The predicted structures were in agreement with surface modification and long-distance crosslinking data. Tau in solution was found as an ensemble of rather compact globular conformations with distinct topology, inter-residue contacts, and a number of transient secondary-structure elements. Regions important for pathological aggregation consistently were found to contain β strands. The determined structures are compatible with the tau protein in solution being a molten globule at near-ground state with persistent residual structural features which we were able to capture by CL-DMD. The predicted structure may facilitate an understanding of the misfolding and oligomerization pathways of the tau protein.
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•441-residue tau protein structure was solved by all-atom DMD simulations•Structural proteomics experimental data were used in protein structure prediction•Tau is a rather compact conformational ensemble with distinct subdomain topology•Extensive β sheet structure was detected in the aggregation-prone R1-R4 repeat regions
Short-distance crosslinking constraint-guided all-atom discrete molecular dynamics simulations (CL-DMD) was used to predict the conformational ensemble of the full-length tau protein in solution. Tau in solution was found to be a fairly compact globular protein that contains persistent structural features in the regions important for pathological aggregation.
Ryanodine receptor 1 (RyR1) is an intracellular calcium ion (Ca2+) release channel required for skeletal muscle contraction. Although cryo‐electron microscopy identified binding sites of three ...coactivators Ca2+, ATP, and caffeine (CFF), the mechanism of co‐regulation and synergy of these activators is unknown. Here, we report allosteric connections among the three ligand‐binding sites and pore region in (i) Ca2+ bound‐closed, (ii) ATP/CFF bound‐closed, (iii) Ca2+/ATP/CFF bound‐closed, and (iv) Ca2+/ATP/CFF bound‐open RyR1 states. We identified two dominant networks of interactions that mediate communication between the Ca2+‐binding site and pore region in Ca2+ bound‐closed state, which partially overlapped with the pore communications in ATP/CFF bound‐closed RyR1 state. In Ca2+/ATP/CFF bound‐closed and ‐open RyR1 states, co‐regulatory interactions were analogous to communications in the Ca2+ bound‐closed and ATP/CFF bound‐closed states. Both ATP‐ and CFF‐binding sites mediate communication between the Ca2+‐binding site and the pore region in Ca2+/ATP/CFF bound—open RyR1 structure. We conclude that Ca2+, ATP, and CFF propagate their effects to the pore region through a network of overlapping interactions that mediate allosteric control and molecular synergy in channel regulation.
We consider two of the most relevant problems that arise when modeling the properties of a tunnel radio communication channel through a plasma layer. First, we studied the case of the oblique ...incidence of electromagnetic waves on a layer of ionized gas for two wave polarizations. The resonator parameters that provide signal reception at a wide solid angle were found. We also took into account the unavoidable presence of a protective layer between the plasma and the resonator, as well as the conducting elements of the antenna system in the dielectric itself. This provides the first complete simulation for a tunnel communication channel. Noise immunity and communication range studies were conducted for a prospective spacecraft radio line.
We examine the effect of resonant absorption of electromagnetic signals in a silicon semiconductor plasma layer when the dielectric plate is placed behind it both experimentally and numerically. It ...is shown that such plate acts as a dielectric resonator and can significantly increase the electromagnetic energy absorption in the semiconductor for certain frequencies determined by the dielectric plate parameters. Numerical modelling of the effect is performed under the conditions of conducted experiment. The numerical results are found to be in qualitative agreement with experimental ones. This study confirms the proposed earlier method of increasing the efficiency of bolometric-type detectors of electromagnetic radiation.
Akt plays indispensable roles in cell proliferation, survival and metabolism. Mechanisms underlying posttranslational modification-mediated Akt activation have been extensively studied yet the Akt ...interactome is less understood. Here, we report that SAV1, a Hippo signaling component, inhibits Akt, a function independent of its role in Hippo signaling. Binding to a proline-tyrosine motif in the Akt-PH domain, SAV1 suppresses Akt activation by blocking Akt's movement to plasma membrane. We further identify cancer-associated SAV1 mutations with impaired ability to bind Akt, leading to Akt hyperactivation. We also determine that MERTK phosphorylates Akt1-Y26, releasing SAV1 binding and allowing Akt responsiveness to canonical PI-3K pathway activation. This work provides a mechanism underlying MERTK-mediated Akt activation and survival signaling in kidney cancer. Akt activation drives oncogenesis and therapeutic resistance; this mechanism of Akt regulation by MERTK/SAV1 provides yet another complexity in an extensively studied pathway, and may yield prognostic information and therapeutic targets.
We have determined conditions when a pair of coupled waveguides, a common element for integrated room-temperature photonics, can act as a qubit based on a system with a double-well potential. ...Moreover, we have used slow-varying amplitude approximation (SVA) for the “classical” wave equation to study the propagation of electromagnetic beams in a couple of dielectric waveguides both analytically and numerically. As a part of an extension of the optical-mechanical analogy, we have considered examples of “quantum operations” on the electromagnetic wave state in a pair of waveguides. Furthermore, we have provided examples of “quantum-mechanical” calculations of nonlinear transfer functions for the implementation of the considered element in optical neural networks.
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