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Identifying SARS-CoV-2 Variants using Single-Molecule Conductance Measurements
No full textThe global COVID-19 pandemic has highlighted the need for rapid, reliable, and efficient detection of biological agents and the necessity of tracking changes in genetic material as new SARS-CoV-2 variants emerge. Here we demonstrate that RNA-based, single-molecule conductance experiments can be used to identify specific variants of SARS-CoV-2. To this end, we i) select target sequences of interest for specific variants, ii) utilize single-molecule break junction measurements to obtain conductance histograms for each sequence and its potential mutations, and iii) employ the XGBoost machine learning classifier to rapidly identify the presence of target molecules in solution with a limited number of conductance traces. This approach allows high specificity and high-sensitivity detection of RNA target sequences less than 20 base pairs in length by utilizing a complementary DNA probe capable of binding to the specific target. We use this approach to directly detect SARS-CoV-2 variants of concerns B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta), and B.1.1.529 (Omicron) and further demonstrate that the specific sequence conductance is sensitive to nucleotide mismatches, thus broadening the identification capabilities of the system. Thus, our experimental methodology detects specific SARS CoV-2 variants, as well as recognizes the emergence of new variants as they arise
Combined Network and High Resolution Mass Spectrometry Analysis of the Formose Reaction Reveals Mechanisms for Emergent Behaviors
No full textThe formose reaction (FR) autocatalytically converts simple plausibly prebiotic feedstocks into molecules of biological interest, including ribose. Autocatalysis is a hallmark of life, thus various studies have explored the formose reaction with respect to the origins of life. The FR is robust under appropriate conditions, occurring readily at low temperatures from various substrates, and has been implicated in the generation of meteoritic organic compounds. We explored the FR here using a combination of in silico modeling techniques and high resolution mass spectrometry. The models match experimental results well, and point to the FR being much more complex than previously modeled or measured, and help explain the FR’s potential to generate homochirality and primitive compartments, both of which are also hallmarks of life, before the emergence of the complex directed molecular encoding suggested by the RNA World model. These results suggest the FR requires further study with regard to the origins of life, and its importance may lie in the way it enables and coordinates emergent chemistries, rather than the particular products it generates, such as ribose
Accessing diverse bicyclic peptide conformations using 1,2,3-TBMB as a linker
No full textBicyclic peptides are a powerful modality for the engagement of challenging drug targets such as protein-protein interactions. The most common crosslinkers used to generate bicyclic peptides are C3-symmetrical, with evenly positioned peptide loops facing radially outwards from a linker core to favour globular conformations. In contrast, linkers with alternative symmetries can potentially provide access to a more diverse conformational landscape of bicyclic peptides. Here, we use 1,2,3-tris(bromomethyl) benzene (1,2,3-TBMB) to access bicyclic peptides with multiple isomeric configurations, leading to conformations that differ substantially from both the parent linear peptides and the conventional bicyclization products formed with 1,3,5-TBMB, as observed in 2D NMR and CD experiments. Bicyclization at cysteine residues proceeds efficiently under standard aqueous buffer conditions, with broad substrate scope, compatibility with high-throughput screening, and clean conversion (>90%) of linear precursors to bicyclic products for 88 of the 106 diverse peptide sequences tested. We envisage that the 1,2,3-TBMB linker will be applicable to a variety of peptide screening techniques, thereby enabling the discovery of unconventional bicyclic peptides that can engage a broad range of novel drug targets
Rationalizing Defective Biomimetic Ceria: In vitro Demonstration of a Potential “Trojan horse” Nanozyme Based-Platform Leveraging Photo-Redox Activities for Minimally Invasive Therapy
No full textMetal oxide nanostructures with surface-defect mediated chemistry have garnered pronounced interest due to the influence of these defects in tuning the photo-induced intracellular bio-catalytic (enzyme-mimicking) responses. However, designing defective nanozymes with pH-responsive multi-bio-catalytic functions without any dopants is challenging. Herein, oxygen-deficient “trojan horse-like” folate-functionalized, L-arginine-coated ceria (FA-L-arg-CeO2) nanozymes with synergistic multi-enzyme-mimicking and anti-cancer potential are introduced. The nanozymes possessed enhanced surface oxygen vacancies (VO●), strategically created under kinetically favourable synthesis conditions. Increased surface VO● promoted band structure reconstruction and amplified photochemical-response efficacy under single laser irradiation (808 nm), outperforming the defect-free commercial nano-CeO2 in rapid anti-tumorigenic activities. Through folate receptor-mediated endocytosis, these biostable nanozymes localized in MDA-MB-231 cells (84% in 48 h) and demonstrated NIR-accelerated enzymatic functions depending on the pH of the biological milieu. The reduced band gap energy facilitated effective electron-hole separation, up-regulating in vitro photo-redox reactions that impart exceptional therapeutic potential and inhibit 62% cell metastasis within only 12 h. By perturbing intratumoural redox homeostasis, VO●-rich FA-L-arg-CeO2 nanozymes unanimously killed 86% of MDA-MB-231 cancer cells while preferentially shielding benign L929 cells. Unlike conventional drug-loaded or dopant-incorporated CeO2 nanoplatforms, these defective multi-modal nanozymes unravel a new avenue for developing smart, low-cost, bio-active agents with enhanced efficacy and bio-safety
Influence of the environment on the infrared spectrum of alanine: an effective modes analysis
No full textThe vibrational spectrum of the alanine amino acid was computationally determined in the infrared range of 1000–2000 cm−1, under various environments encompassing the gas, hydrated, and crystalline phases, by means of classical molecular dynamics trajectories carried out with the AMOEBA polarizable force field. An effective mode analysis was performed in which the spectra are optimally decomposed into different absorption bands arising from well-defined internal modes. In the gas phase, this analysis allows to unravel the significant differences between the spectra obtained for the neutral and zwitterionic forms of the amino acid. In condensed phases, the method provides invaluable insight into the molecular origins of the vibrational bands and further shows that peaks with similar positions can be traced to rather different molecular motions
Density functional theory for van der Waals complexes: Size matters
No full textOver the past 25 years there has been remarkable progress towards accurate description of nonbonded interactions within the context of density functional theory (DFT). Various methods have been devised to capture London dispersion, which is the most exacting contribution to noncovalent interactions; these strategies include both new functionals as well as ad hoc dispersion corrections to existing functionals. At present, it is possible to compute interaction energies for small van der Waals complexes (containing ~20 atoms) to an accuracy of ~0.5 kcal/mol, using a range of dispersion-inclusive DFT methods that are reviewed here. Systematic tests reveal remarkable consistency across different methods, at least for small noncovalent dimers. At the same time, the magnitude of the ad hoc dispersion corrections are systematically smaller than benchmark dispersion energies because some dispersion resides within the semilocal exchange-correlation functional, in a manner that is difficult to disentangle. Despite impressive results for small systems, the best contemporary DFT methods afford larger errors in systems with >~ 100 atoms, approaching 3-5 kcal/mol as compared to ab initio benchmarks for total interaction energies, although the benchmarks themselves have larger uncertainties in systems of this size. Errors for larger systems vary widely from one DFT method to the next, with no discernible systematic trend. Nanoscale van der Waals complexes thus represent the new frontier in development of DFT for noncovalent interactions
Using Chiral Auxiliaries to Mimic the Effect of Chiral Media on the Structure of Lanthanide(III) Complexes Common in Bioimaging and Diagnostic MRI
No full text[Ln·DOTA]- complexes, and systems derived therefrom, are commonly used in MRI and optical bioimaging. These lanthanide(III) complexes are chiral and, in solution, they are present in eight forms, two sets of four uncapped and four capped forms. Each set of four consist of two sets of enatiomers, with the ligand backbone in either a square antiprismatic, SAP, or twisted square antiprismatic geometry, TSAP. This complex speciation is found in laboratory samples. To investigate speciation in biological media, when Ln·DOTA-like complexes interact with chiral biomolecules, six Eu·DOTA-monoamide complexes were prepared and investigated using 1D and 2D 1H NMR. To emulate the chirality of biological media, the amide pendant arm was modified with one or two chiral centers. It was known that a chiral center on the DOTA scaffold significantly influences the properties of the system. Here, it was found that chirality much further away from the metal changes the available conformational space, and that both chiral centers and cis/trans isomerism are important, a fact that, for the optically pure materials, led to the conclusion that sixteen forms had to be considered, instead of the eight forms necessary for DOTA. The results reported here clearly demonstrate the diverse speciation that must be considered when correlating an observation to a structure of a lanthanide(III) complex
π-System Bistability Determines the Circularly Polarized Luminescence in Helicene para-Phenylenes
No full textWe resolve the origin of the anomalous circularly polarized luminescence (CPL) observed in helicene para-phenylenes (HPPs), a new class of chiral macrocyclic nanocarbons reported recently. We show by synthesis of HPPs that embed [5]helicene unit that the presence of two emission bands in the CPL, each with the opposite handedness, relates to the topological bistability of their π-electron system. This bistability allows the HPPs to adopt Möbius and Hückel conformations that differ in the orientability of their π-system. We demonstrate that the bistability can be controlled by molecular strain and it can be effectively used to turn off one of the emissions. Our work is thus the first to report that the topological bistability of π-electron system can dramatically impact the chiroptical properties in single-stranded Möbius molecular nanocarbons. In addition, we demonstrate that the parity of the number of π-electrons in the delocalization paths in the doubly-oxidized HPPs with [5]helicenes permits induction of global ring currents, i.e., these compounds may display global (anti)aromaticity
Molecularly Shielded, On-Demand, Ultrasound-Cured Polymer Networks
No full textNetworks formed from polymers can range from soft hydrogels to ultrahard protective coatings, making them useful for a wide range of applications from cell culture to highly bonded adhesives. Polymer networks are commonly crosslinked via heat or high energy light, and recently mechanical force has also been used to induce the formation of crosslinks in pre-existing networks. Here, we demonstrate a new strategy to use mechanical deformation and ultrasound to induce liquid-to-solid crosslinking. We synthesized graft copolymers with large poly(ethylene glycol) (PEG) side-chains acting as molecular shielding groups to protect otherwise highly reactive epoxide group. Solutions of highly shielded polymers could remain as a liquid solution when left undisturbed , and we could initiate gelation of these solutions with ultrasound in 20 seconds. These ultrasound-sensitive polymers are particularly useful in light and heat sensitive applications, and where precise control over the gelation time is required
Assessing the progress of the performance of continuous monitoring solutions under single-blind controlled testing protocol
No full textRecent regulatory spotlight on continuous monitoring (CM) solutions and the rapid development of CM solutions has demanded the characterization of solutions performance through regular, rigorous testing using consensus test protocols. This study is the second known implementation of such protocol involving single-blind controlled testing of 9 CM solutions. Controlled releases of rates (6 to 7100) g CH4/h over durations (0.4 to 10.2) hours under wind speed range of (0.7 to 9.9) m/s were conducted for 11 weeks. Results showed that 4 solutions achieved method detection limits (DL90s) within tested emission rate range with all 4 solutions having both the lowest DL90s (3.9 [3.0, 5.5] kg CH4/h to 6.2 [3.7, 16.7] kg CH4/h) and false positive rates (6.9% to 13.2%) indicating efforts at balancing low sensitivity with low false positive rate. Quantification results showed wide individual estimate uncertainties with emissions underestimation and overestimation by factors up to > 14 and 42 respectively. Three solutions had > 80% of their estimates within a quantification factor of 3 for controlled releases in the ranges of (0.1 – 1] kg CH4/h and >1 kg CH4/h. Relative to the study by Bell et al., current solutions performance, as a group, generally improved primarily due to solutions from the study by Bell et al. that retested. This result highlights the importance of regular, quality testing to the advancement of CM solutions for effective emissions mitigation