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A Dataset of Simple 1-D and 2-D NMR Spectra of Peptides, Including all Encoded Amino Acids, for Introductory Instruction in Protein Biomolecular NMR Spectroscopy
No full textNMR spectroscopy is the most important technique for understanding the structure of peptides and proteins in solution, providing information at the single-residue and single-atom level. However, written instruction in the interpretation of NMR spectra of peptides and proteins is generally focused on advanced techniques and highly complex spectra, with a lack of simple spectra and guides available for beginning students. In order to address this instructional limitation, we have generated a dataset of 1H NMR spectra of a series of simple peptides that include all canonical amino acids. Peptides examined include Ac-X(S/pS)-NH2, Ac-X(T/pT)-NH2, and Ac-XPPGY-NH2, where X = all encoded amino acids, pS = phosphorylated Ser, and pT = phosphorylated Thr. The characterization of each peptide includes a 1-D spectrum and a TOCSY spectrum, with both the raw and processed available. The spectra can be used for instructional applications including analysis of regions of the spectra (e.g. amide HN, aromatic, Hα, and aliphatic regions); identification of spin systems and residue assignment via TOCSY spectra; analysis of conformational features including amide HN chemical shift dispersion and changes due to hydrogen bonding or post-translational modifications; the 3JαN coupling constant that reports on the φ torsion angle and on order versus disorder at a given residue; conformational preferences at Hα via chemical shift index analysis; understanding of diastereotopic hydrogens; dynamic processes, including hydrogen exchange; and identification of proline cis-trans isomerism. In addition, for a limited number of peptides, NOESY spectra are included to allow sequential resonance assignment and for assignment of trans versus cis proline conformations. Spectra from closely related peptides allow the analysis of the relative effects of single amino acid changes. The paper is written to be directly accessible to students as a tutorial guide. In addition, the data can be used by instructors for problem sets and exams
Boronic acid linked CPP for protein delivery
No full textStudying functional protein delivery into live cells is important, ranging from fundamental research to therapeutics. Cell-penetrating peptides (CPPs) are known to deliver proteins with applauded efficacy and have gained importance for applications in protein therapeutics and exploring versatile cellular mechanisms. The primary aim of the work is to design a CPP as a tool/delivery vehicle for macromolecules, including proteins. In this work, boronic acid-linked cyclic deca arginine (cR10) is reported as an efficient CPP that exhibited threefold higher delivery of chemically synthesized ubiquitin (Ub) than pristine cR10-linked Ub, examined with live U2OS cells. As a futuristic plan, artificial intelligence machine learning-based rationale has been designed and proposed
Thermal Truncation of Heptamethine Cyanine Dyes
No full textCyanine dyes are a class of organic, usually cationic molecules containing two nitrogen centers linked through conjugated polymethine chains. Unlike phototruncation, the thermal truncation (chain-shortening) reaction is a phenomenon that has rarely been described for these important fluorophores. Here, we present a systematic investigation of the truncation of heptamethine cyanines (Cy7) to pentamethine (Cy5) and trimethine (Cy3) cyanines via homogeneous, acid-base catalyzed nucleophilic exchange reactions. We demonstrate how different substituents at the C3′ and C4′ positions of the chain and dif-ferent heterocyclic end groups, the presence of different bases, nucleophiles and oxygen, solvent properties, and tempera-ture affect the truncation process. The mechanism of chain shortening, studied by various analytical and spectroscopic techniques, was verified by extensive ab initio calculation, demonstrating the need to model catalytic reactions by highly correlated wavefunction-based methods. We show that entropic effects control the course of this process. The study provides a critical insight into the reactivity of the polyene chains of cyanines and offers new approaches to the synthesis of meso-substituted symmetrical and unsymmetrical pentamethine cyanines from Cy7 derivatives
Can Large Language Models Predict Antimicrobial Peptide Activity and Toxicity?
No full textAntimicrobial peptides (AMPs) are naturally occurring or designed peptides up to a few tens of amino acids which may help address the antimicrobial resistance crisis. However, their clinical development is limited by toxicity to human cells, a parameter which is very difficult to control. Given the similarity between peptide sequences and words, large language models (LLMs) might be able to predict AMP activity and toxicity. To test this hypothesis, we fine-tuned LLMs using data from the Database of Antimicrobial Activity and Structure of Peptides (DBAASP). GPT-3 performed well but not reproducibly for activity prediction and hemolysis, taken as a proxy for toxicity. The later GPT-3.5 performed more poorly and was surpassed by recurrent neural networks (RNN) trained on sequence-activity data or support vector machines (SVM) trained on MAP4C molecular fingerprint-activity data. These simpler models are therefore recommended, although the rapid evolution of LLMs warrants future re-evaluation of their prediction abilities
Experimentally Delineating the Catalytic Effect of a Single Water Molecule in the Photochemical Rearrangement of the Phenylperoxy Radical to the Oxepin-2(5H)-one-5-yl Radical
No full textCatalysis plays a pivotal role in both chemistry and biology, primarily attributed to its ability to stabilize transition states and lower activation free energies, thereby accelerating reaction rates. While computational studies have contributed valuable mechanistic insights, there remains a scarcity of experimental investigations into transition states. In this work, we embark on an experimental exploration of the catalytic energy lowering associated with transition states in the photo-rearrangement of the phenylperoxy radical-water complex to the oxepin-2(5H)-one-5-yl radical. Employing matrix isolation spectroscopy, density functional theory (DFT), and post-HF computations, we scrutinize the (photo)catalytic impact of a single water molecule on the rearrangement. Our computations indicate that the barrier heights for the water-assisted unimolecular isomerization steps are approximately 2–3 kcal mol–1 lower compared to the uncatalyzed steps. This decrease directly coincides with the difference in the required wavelength during the transformation (Δλ = λ579nm – λ546nm ~ 3 kcal mol–1)), allowing us to elucidate the transition state energy in the photochemical rearrangement of the phenylperoxy radical catalyzed by a single water molecule. Our work highlights the important role of water catalysis and has, amongst others, implications for understanding the mechanism of organic reactions under atmospheric conditions
Unimolecular Chemiexcited Oxygenation of Pathogenic Amyloids
No full textPathogenic protein aggregates, called amyloids, are etiological-ly relevant to various diseases, including neurodegenerative Alzheimer disease. Catalytic photooxygenation of amyloids, such as amyloid-β (Aβ), reduces their toxicity; however, the requirement for light irradiation may limit its utility in large animals, including humans, due to the low tissue permeability of light. Here, we report that Cypridina luciferin analogs, dmCLA-Cl and dmCLA-Br, promoted selective oxygenation of amyloids through chemiexcitation without external light irra-diation. Further structural optimization of dmCLA-Cl led to the identification of a derivative with a polar carboxylate functional group and low cellular toxicity: dmCLA-Cl-acid. dmCLA-Cl-acid promoted oxygenation of Aβ amyloid and reduced its cellular toxicity without photoirradiation. The chemiexcited oxygenation developed in this study may be an effective approach to neutralizing the toxicity of amyloids, which can accumulate deep inside the body, and treating amy-loidosis
Thermal Ca^2+/Mg^2+ Exchange Reactions to Transform Abundant Silicates Into Alkaline Materials for Carbon Dioxide Removal
No full textThe removal of CO2 from the atmosphere (CDR) on the multi-hundred gigaton (Gton) scale is essential for nearly all strategies to achieve net-zero greenhouse gas emissions and limit global warming to 2°C by 2100. CDR must capture CO2 from air and safely sequester it. Mg-rich silicate minerals have the capacity to remove ~10^5 Gton CO2 and sequester it in the form of stable and innocuous carbonate minerals or dissolved bicarbonate ions, but their reaction rates under ambient conditions are far too slow for practical and scalable CDR. Here we show that CaO reacts quantitatively with diverse Mg silicates (olivine, serpentine, augite) under thermochemical conditions to form Ca2SiO4 and MgO. Upon exposure to ambient air under wet conditions, Ca2SiO4 is quantitatively converted to CaCO3 and SiO2, and MgO is partially converted into a Mg carbonate within weeks, while the input Mg silicate shows no reactivity over 6 months. The mixture of Ca2SiO4, and MgO can also be completely carbonated to CaCO3 and Mg(HCO3)2 under 1 atm CO2 at ambient temperature within hours. By combining it with CaCO3 calcination to generate CaO, this chemistry enables a new process for CDR wherein the output Ca2SiO4/MgO material is used to remove CO2 from air or soil to form stable (bi)carbonates and the CO2 process emissions are sequestered. Analysis of the energy requirements indicates that this process could provide CDR at less than 1 MWh per ton CO2 removed, approximately half the energy required just to capture CO2 with leading direct air capture technologies. We also demonstrate analogous transformations using CaSO4 as the CaO source. The chemistry described here could unlock the use of Mg-rich silicates as a vast resource for safe, permanent, and verifiable CDR
Pd(COD)(DQ): A Stable, Versatile, and Monometallic Palladium(0) Source for Organometallic Synthesis and Catalysis
No full textPd(COD)(DQ) (COD=1,5-cyclooctadiene, DQ=duroquinone) is a robust, air-stable, and well-defined 18-electron Pd(0)–olefin complex first synthesized by Sakai et al. in 1983. Herein, we describe an operationally convenient synthetic procedure to prepare this complex on decagram scale; we show that it undergoes facile ligand exchange with phosphines, N-heterocyclic carbenes, and other catalytically important ancillary ligands to give stable organometallic products; and we demonstrate its catalytic competence in numerous useful reactions in organic synthesis. We anticipate that the pronounced stability of Pd(COD)(DQ) and its favorable handling properties will allow it to find use as a convenient Pd(0) source in academic and industrial research labs
Charge compensation and structural adaptation to accommodate increased magnetic cation content in multiferroic Aurivillius phases
No full textThe five-layered (m = 5) Bi6Ti2.99Fe1.46Mn0.55O18 Aurivillius material is a rare example of a single-phase room temperature ferroelectric-ferromagnetic multiferroic that could ideally be suited to future energy-efficient memory devices. This study examines the effect of B-site substitution with the aim of increasing the proportion of magnetic ions within the structure and consequently increasing the saturation magnetisation. Four series of Aurivillius phase films with a target composition of Bi6TixFeyMnzO18 (B6TFMO; x = 2.3 to 3.2, y = 1.2 to 2.0, z = 0.3 to 0.9) were fabricated by chemical solution deposition. Substitution of Ti4+ by Fe3+ and Mn3+ necessitates charge compensation mechanisms and requires accommodation of differing ionic radii. While valence changes of Mn3+ to Mn4+ can act to compensate charge, XRD and TEM analysis is used here to demonstrate that above a threshold of 8 % nominal Mn4+, the m = 5 structure can no longer accommodate the smaller Mn4+ ion and it rearranges into a mixed-phase material based on m = 5 and six-layered (m = 6) inter-growths. Increasing the number of perovskite layers by forming the m = 6 structure facilitates the accommodation of additional magnetic cations at a lower average manganese oxidation state (+3.3). This work provides valuable insight into the design and development of versatile multiferroic phases by describing how the B-site magnetic cation content can be increased to 54 % in m = 6 structures, compared to a solubility limit of 46 % in m = 5 structures
High-resolution 17O solid-state NMR as a unique probe for investigating oxalate binding modes in materials: The case study of calcium oxalate biominerals
No full textOxalate ligands are found in many classes of materials, including energy-storage materials and biominerals like hydrated calcium-oxalates. Determining their local environments at the atomic scale is thus paramount to establishing the structure and properties of numerous phases. Here, we show that high-resolution 17O solid-state NMR is a valuable asset for investigating the structure of crystalline oxalate systems. First, an efficient 17O-enrichment procedure of oxalate ligands is demonstrated using mechanochemical saponification. Then, the use of 17O-enriched oxalates for the synthesis of the biologically relevant calcium-oxalate monohydrate (COM) phase is presented, enabling the analysis of its structure and heat-induced phase transitions by high-resolution 17O solid-state NMR. NMR studies of the low-temperature COM form (LT-COM), using magnetic fields varying from 9.4 to 35.2 T, as well as 13C-17O MQ/D-RINEPT and 17O{1H} MQ/REDOR experiments, enabled the 8 inequivalent oxygen sites of the oxalate ligands to be resolved, with a tentative assignment proposed. Then, the structural changes occurring upon heat treatment of COM were followed by high-resolution 17O solid-state NMR, providing new insight into the structures of the high-temperature form (HT-COM) and anhydrous calcium oxalate alpha-phase (alpha-COA), including the presence of structural disorder in the latter case. Overall, this work highlights the ease associated with 17O-isotopic enrichment of oxalate oxygens, and how it enables the study of oxalate structures (including materials of biological relevance) at high-resolution via solid-state NMR, in the frame of “NMR-crystallography” investigations