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Selecting Reducing Agents for Native Mass Spectrometry
No full textIn protein science, reducing agents are often added in cases where the protein, its cofactors, or its ligands are sensitive to oxidative stress. Although many native mass spectrometry (MS) workflows would benefit from maintaining reducing conditions throughout the analysis, there is a lack of consensus regarding the compatibility of reducing agents with that approach. This study systematically examines the effects of dithiothreitol (DTT), β-mercaptoethanol (βME), and tris(2-carboxyethyl)phosphine (TCEP) on the native mass spectra of protein standards. The selection and concentration of the reducing agents affected both the extent of nonspecific adduction and the charge-state distribution of the analyte. For a protein without disulfide bonds, increasing concentrations of DTT or βME resulted in shifts to higher charge states, whereas increasing concentrations of TCEP resulted in shifts to lower charge states. Based on these trends and additional properties of the reducing agents, we propose that DTT and βME are mild supercharging agents and that TCEP is a potent charge-reducing agent. The selection and concentration of the reducing agents, as well as the sample pH, also affected the extent of disulfide bond reduction, and for βME, the extent of covalent adduction by that molecule to cysteine. These results offer insights into the compatibility of reducing agents with the goal of obtaining high-quality native mass spectra. Based on our results, we present recommendations for the use of reducing agents in native MS experiments
Communication efficiency enhanced federated learning derived from quantum reinforcement learning for retrosynthesis
No full textThe combination of parametric quantum circuits and density matrix coding can significantly reduce the number of parameters in artificial neural networks. The reduction in the number of model parameters helps to improve the commu- nication efficiency when training deep learning models under federated learning architectures. In this study, we showcase the enhanced communication efficiency achieved in federated learning by utilizing quantum neural networks in the context of the molecular inverse synthesis task within reinforcement learning. Specifically, we consider the federated learning task on the reinforcement learning-based retrosynthesis. we adopted the USPTO-50k chemical reaction dataset. the MLP and quantum neural network are used as the agent of the reinforcement learning algorithm, respectively. Enhancements in communica- tion efficiency stem from the capacity of encoded quantum states within quantum neural networks to effectively represent data. All instances are additionally situated within the framework of ligand molecules associated with Tau proteins
Gravesoil derived postmortem interval using attenuated total reflectance-Fourier transform infrared spectroscopy and the influence of carrion-associated fabric.
No full textEstablishing time elapsed for unattended death scenes is crucial in formulating a timeline of events facilitating death investigations. However, traditional postmortem interval (PMI) methods rely on visually evaluating physical atrophy and are closely influenced by both biotic and abiotic variables associated with carrion. During the bloat stage, carrion produces a characteristic landscape known as the cadaver decomposition island (CDI), through the
propagation of fluids rich in decomposition by-products. Here, attenuated total reflectance- Fourier transform infrared spectroscopy (ATR-FT-IR) was employed as a non-invasive, low input, low preparation interface for determining PMI from simulated Mus musculus burial gravesoil. Furthermore, understanding the influences of environmental and inter-individual differences in gaining accurate PMI is important to validate, prior to implementation to enhance the current forensic toolkit. It is documented that the presence, type and weight of clothing interferes with progression through decomposition. The subsequent impacts of clothing material (cotton, polyester, viscose) on CDI footprint development will be reflected in the biological and chemical characteristics of this ecosystem. Principal component analysis (PCA) of the IR spectra showed two clusters of samples corresponding to control and gravesoil. PC loadings plot showed that the 3100 - 1000 cm-1 spectral range attributed for over 95% of the variance. Bands within this range are ascribed to the presence of lipids, proteins and volatile organic compounds (VOCs) as byproducts of mammalian decomposition. Overall, presence and fabric type impacted decomposition, spectral CDI detection and grave discrimination. This
study questions the efficacy of proxy size and microcosm design in conducting applicable forensic research in lieu of taphonomy facilities or ethical constraints
Photochemical Formation and Electronic Structure of an Alkane -Complex from Time-Resolved Optical and X-ray Absorption Spectroscopy
No full textC-H bond activation reactions with transition metals typically proceed via the formation of alkane -complexes, where an alkane C-H -bond binds to the metal. Due to the weak nature of metal-alkane bonds, -complexes are challenging to characterize experimentally. Here, we photochemically prepare the model -complex Cr(CO)5-alkane from Cr(CO)6 in octane solution and characterize the nature of its metal-ligand bonding interactions. Using femtosecond optical absorption spectroscopy, we find photo-induced CO dissociation from Cr(CO)6 to occur within the 100 fs time-resolution of the experiment. Rapid geminate recombination by a fraction of molecules is found to occur with a time constant of 150 fs. The formation of bare Cr(CO)5 in its singlet ground state is followed by complexation of an octane molecule from solution with a time constant of 8.2 ps. Picosecond X-ray absorption spectroscopy at the Cr L-edge and O K-edge provides unique information on the electronic structure of the Cr(CO)5-alkane -complex both from the metal and ligand perspectives. We find substantial destabilization of the lowest unoccupied molecular orbital upon coordination of the C-H bond to the undercoordinated Cr center in the Cr(CO)5-alkane -complex, accompanied with rehybridization between metal and ligand orbitals. Our study demonstrates the value of combining optical and X-ray spectroscopic methods as complementary tools to study the properties of alkane -complexes as the decisive intermediates in C-H bond activation reactions
Chiral π-Conjugated Double Helical Aminyl Diradical with Triplet Ground State
No full textWe report a neutral high-spin diradical of chiral C2-symmetric bis[5]diazahelicene with ΔEST ≈ 0.4 kcal mol-1, as determined by EPR spectroscopy/SQUID magnetometry. The diradical is the most persistent among all high-spin aminyl radicals reported to date by a factor of 20, with a half-life up to 6 days in 2-MeTHF at room temperature. Its triplet ground state and excellent persistence may be associated with the unique spin density distribution within the dihydrophenazine moiety, characterizing two effective 3-electron C-N bonds analogous to the N-O bond of nitroxide radical. The enantiomerically enriched (ee ≥ 94%) (MM)- and (PP)-enantiomers of the precursors to the diradicals are obtained by either preparative chiral supercritical flow chromatography (SFC) or resolution via functionalization with chiral auxiliary of the C2-symmetric racemic tetraamine. The barrier for racemization of the solid tetraamine is ΔG‡ = 43 ± 0.01 kcal mol-1 in the 483 – 523 K range. The experimentally estimated lower limit of the barrier for racemization of diradical, ΔG‡ ≥ 26 kcal mol-1 in 2-MeTHF at 293 K, is comparable to the DFT-determined barrier of ΔG‡ = 31 kcal mol-1 in the gas phase at 298 K. While the enantiomerically pure tetraamine displays strong chiroptical properties, with anisotropy factor |g| = |Δε|/ε = 0.036 at 376 nm, |g| ≈ 0.005 at 548 nm of the high-spin diradical is comparable to that recently reported triplet ground state diradical dication. Notably, the radical anion intermediate in the generation of diradical exhibits large SOMO-HOMO inversion, SHI = 35 kcal mol-1
Selection of DNA-encoded Chemical Libraries for Compounds that can Induce Protein Ubiquitination
No full textWe report a selection method of DNA-encoded libraries (DELs) that can identify the compounds able to induce ubiquitination of the protein of intertest (POI). Since the selection readout of the method is based on POI ubiquitination, rather than POI binding or ternary complex formation, the identified compounds are more functionally relevant and more predicative of active protein degraders. In this study, by selecting a DEL of 950 different combinations of POI ligands, linkers, and E3 ligase ligands against the BD1 domain of bromodomain-containing protein 4 (BRD4-BD1) in the presence and absence of ATP, we have identified a potent BRD4-BD1 degrader (DC50: ~9.7 nM) and also a short-isoform-selective BRD4 degrader (DC50: 0.26 μM). Furthermore, we show that the selection based on POI binding or ternary complex formation identified compounds that may have induced stable complexes but are inactive degraders. This approach may be an efficient and broadly applicable method for discovering functional protein degraders, as well as E3 ligase ligands, by harnessing the vast chemical diversity of DELs
Kinetic barrier networks reveal rate limitations in ion selective membranes
No full textWhile polymer membranes are used to remove salts from environmental and industrial electrolytes, it remains a significant challenge to engineer them to isolate a single dissolved species from complex mixtures, which is important for lithium mining, battery and magnet recycling, and microelectronics. Underpinning this challenge has been a lack of understanding of rate-limiting mechanisms in selective ion transport. Here, we show that hydrated ions exhibit higher free energies of activation when crossing solution–membrane interfaces (i.e., partitioning) than when diffusing through polymers, which challenges historical assumptions embedded in widely used models of membrane performance. We further articulate a framework benchmarked with quantitative capabilities for predicting how functionality within polymer membranes or at their surfaces affects the selectivity towards individual dissolved species
Ru(II)-catalyzed C7 trifluoromethylthiolation and thioaryla-tion of indolines using bench-stable reagents
No full textA Ru(II)-catalyzed C(sp2)-H trifluoromethylthiolation and thioarylation of indolines using bench-stable reagents have been explored. Diversely substituted indolines were successfully functionalized at C7 position in good to excellent yields. To support the proposed reaction pathway, radical quenching, deuterium labeling, KIE experiments, and reac-tion order determination were performed. Gram-scale synthesis and post-transformation of the synthesized product have also been performed to demonstrate the applicability of the developed catalytic protocol
Synthesis of Substituted Triazole-Pyrazole Hybrids using Triazenopyrazoles Precursors
No full textA synthesis route to access triazole-pyrazole hybrids via pyrazolotriazenes was developed. Contrary to existing methods, this route allows the facile N-functionalization of the pyrazole before the attachment of the triazole unit via a copper-catalyzed azide-alkyne cycloaddition. The developed methodology was used to synthesize a library of over fifty novel multi-substituted pyrazole-triazole hybrids. We could also demonstrate a one-pot strategy that renders the isolation of potentially hazardous azides obsolete. In addition, the compatibility of the method with solid-phase synthesis was shown exemplarily
Tracking Coordination Environment and Reaction Intermediates in Homo- and Heterogeneous Epoxidation Catalysts via Ti L2,3-edge NEXAFS
No full textTi-based molecules and materials are ubiquitous, and play a major role in both homogeneous and heterogeneous catalytic processes. Understanding the electronic structures of their active sites (oxidation state, local symmetry and ligand environment) is key to developing molecular-level structure-property relationships. In that context, X-ray absorption spectroscopy (XAS) offers a unique combination of element selectivity and sensitivity to local symmetry. Commonly, for early transition metals such as Ti, K-edge XAS is applied for in situ characterization and subsequent structural analysis with high sensitivity towards tetrahedral species. Ti L2,3-edge spectroscopy is in principle complementary and offers specific opportunities to interrogate the electronic structure of five-and six-coordinated species. It is, however, much more rarely implemented, because the use of soft X-rays implies ultra-high vacuum conditions. Furthermore, the interpretation of the data can be challenging. Here, we show how Ti L2,3-edge spectroscopy can help to obtain unique information about both homogenous and heterogeneous epoxidation catalysts and to develop a molecular-level relationship between spectroscopic signatures and electronic structures. Towards this goal, we first establish a spectral library of molecular Ti reference compounds, comprising various coordination environments with mono- and dimeric Ti species having O, N and Cl-ligands. We next implemented a computational methodology based on multiplet ligand field theory and maximally localized Wannier orbitals benchmarked on our library to understand Ti L2,3-edge spectroscopic signatures. We finally used this approach to track and predict spectra of catalytically relevant intermediates, focusing on Ti-based olefin epoxidation catalysts