Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19. SARS-CoV-2 relies on cellular RNA-binding proteins (RBPs) to replicate and spread, although which RBPs control its life cycle remains largely unknown. Here, we employ a multi-omic approach to identify systematically and comprehensively the cellular and viral RBPs that are involved in SARS-CoV-2 infection. We reveal that SARS-CoV-2 infection profoundly remodels the cellular RNA-bound proteome, which includes wide-ranging effects on RNA metabolic pathways, non-canonical RBPs and antiviral factors. Moreover, we apply a new method to identify the proteins that directly interact with viral RNA, uncovering dozens of cellular RBPs and six viral proteins. Amongst them, several components of the tRNA ligase complex, which we show regulate SARS-CoV-2 infection. Furthermore, we discover that available drugs targeting host RBPs that interact with SARS-CoV-2 RNA inhibit infection. Collectively, our results uncover a new universe of host-virus interactions with potential for new antiviral therapies against COVID-19.
A note on versions:The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription.For more information, please contact eprints@nottingham.ac.uk *To whom correspondence should be addressed. Email: Tim.Wright@nottingham.ac.uk AbstractWe give a description of the phenyl-ring-localized vibrational modes of the ground states of the paradisubstituted benzene molecules including both symmetric and asymmetric cases. In line with others,we quickly conclude that the use of Wilson mode labels is misleading and ambiguous; we conclude the same regarding the related ones of Varsányi. Instead we label the modes consistently based upon the Mulliken (Herzberg) method for the modes of para-difluorobenzene (pDFB). Since we wish the labelling scheme to cover both symmetrically-and asymmetrically-substituted molecules, we apply the Mulliken labelling under C 2v symmetry. By studying the variation of the vibrational wavenumbers with mass of the substituent, we are able to identify the corresponding modes across a wide range of molecules and hence provide consistent assignments. Particularly interesting are pairs of vibrations that evolve from in-and out-of-phase motions in pDFB to more localized modes in asymmetric molecules. We consider the para isomers of the following: the symmetric dihalobenzenes, xylene, hydroquinone, the asymmetric dihalobenzenes, halotoluenes, halophenols and cresol.Keywords: Frequencies; Ground state; Substituted benzenes. 2 I. INTRODUCTIONBecause an understanding of the trends in the vibrational spectroscopy and dynamics of molecules is linked to being able to refer to the same vibrational motions (normal modes) across species, it is desirable to label these in as consistent a manner as possible. In this way, when referring to a labelled vibration in one molecule, one can be sure of talking about the same vibration in a different molecule.Since there are a whole range of substituted benzenes, it has been very common to refer to the phenylring-localized vibrations of any such molecule in terms of the vibrations of the parent benzene molecule via the Wilson labelling scheme [1]. In previous work on the monosubstituted benzenes it has been noted by our group [2] and others [3,4] that in fact the use of the Wilson labelling scheme is fraught with uncertainty owing to the large differences between the forms of the normal modes of benzene and those of the monosubstituted species; this difference occurs even for the substitution of H for D in monodeuterated benzene [2]. This has been recognized by many workers, perhaps most notably Varsányi [5], who attempted to bring consistency to the labelling by proposing Wilson-type labels for a whole range of substituted benzenes; unfortunately, however, this was hampered by incomplete data sets, and there was also inconsistency conce...
Ab initio calculations were employed to determine the geometry (MP2 level), and dissociation energies [MP2 and RCCSD(T) levels], of the M(IIa)(+)-RG2 species, where M(IIa) is a group 2 metal, Be or Mg, and RG is a rare gas (He-Rn). We compare the results with similar calculations on M(Ia)(+)-RG2, where M(Ia) is a group 1 metal, Li or Na. It is found that the complexes involving the group 1 metals are linear (or quasilinear), whereas those involving the group 2 metals are bent. We discuss these results in terms of hybridization and the various interactions in these species. Trends in binding energies, D(e), bond lengths, and bond angles are discussed. We compare the energy required for the removal of a single RG atom from M(+)-RG2 (D(e2)) with that of the dissociation energy of M(+)-RG (D(e1)); some complexes have D(e2) > D(e1), some have D(e2) < D(e1), and some have values that are about the same. We also present relaxed angular cuts through a selection of potential energy surfaces. The trends observed in the geometries and binding energies of these complexes are discussed. Mulliken, natural population, and atoms-in-molecules (AIM) population analyses are performed, and it is concluded that the AIM method is the most reliable, giving results that are in line with molecular orbital diagrams and contour plots; unphysical amounts of charge transfer are suggested by the Mulliken and natural population approaches.
. (2014) Vibrations of the S1 state of fluorobenzene-h5 and fluorobenzene-d5 via resonanceenhanced multiphoton ionization (REMPI) spectroscopy. Journal of Chemical Physics, 141 (24 A note on versions:The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription. We report resonance-enhanced multiphoton ionization spectra of the isotopologues fluorobenzeneh 5 and fluorobenzene-d 5 . By making use of quantum chemical calculations, the changes in the wavenumber of the vibrational modes upon deuteration are examined. Additionally, the mixing of vibrational modes both between isotopologues and also between the two electronic states is discussed. The isotopic shifts lead to dramatic changes in the appearance of the spectrum as vibrations shift in and out of Fermi resonance. Assignments of the majority of the fluorobenzene-d 5 observed bands are provided, aided by previous results on fluorobenzene-h 5 . C 2014 AIP Publishing LLC.[http://dx
The form of molecular vibrations, and changes in these, give valuable insights into geometric and electronic structure upon electronic excitation or ionization, and within families of molecules. Here, we give a description of the phenyl-ring-localized vibrational modes of the ground (S0) electronic states of a wide range of orthodisubstituted benzene molecules including both symmetrically-and asymmetrically-substituted cases. We conclude that the use of the commonly-used Wilson or Varsányi mode labels, which are based on the vibrational motions of benzene itself, is misleading and ambiguous. In addition, we also find the use of the Mi labels for monosubstituted benzenes [A. M. Gardner and T. G. Wright. J. Chem. Phys. 135 (2011) 114305], or the recently-suggested labels for para-disubstituted benzenes [A. Andrejeva, A. M. Gardner, W. D. Tuttle, and T. G. Wright, J. Molec. Spectrosc. 321, 28 (2016)] are not appropriate. Instead, we label the modes consistently based upon the Mulliken (Herzberg) method for the modes of ortho-difluorobenzene (pDFB)under Cs symmetry, since we wish the labelling scheme to cover both symmetrically-and asymmetricallysubstituted molecules. By studying the vibrational wavenumbers from the same force field while varying the mass of the substituent, we are able to identify the corresponding modes across a wide range of molecules and hence provide consistent assignments. We assign the vibrations of the following sets of molecules: the symmetric o-dihalobenzenes, o-xylene and catechol (o-dihydroxybenzene); and the asymmetric odihalobenzenes, o-halotoluenes, o-halophenols and o-cresol. In the symmetrically-substituted species, we find a pair of in-phase and out-of-phase carbon-substituent stretches, and this motion persists in asymmetricallysubstituted molecules for heavier substituents. When at least one of the substituents is light, then we find that these evolve into localized carbon-substituent stretches.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19. SARS-CoV-2 relies on cellular RNA-binding proteins (RBPs) to replicate and spread, although which RBPs control SARS-CoV-2 infection remains largely unknown. Here, we employ a multi-omic approach to identify systematically and comprehensively which cellular and viral RBPs are involved in SARS-CoV-2 infection. We reveal that the cellular RNA-bound proteome is remodelled upon SARS-CoV-2 infection, having widespread effects on RNA metabolic pathways, non-canonical RBPs and antiviral factors. Moreover, we apply a new method to identify the proteins that directly interact with viral RNA, uncovering dozens of cellular RBPs and six viral proteins. Amongst them, several components of the tRNA ligase complex, which we show regulate SARS-CoV-2 infection. Furthermore, we discover that available drugs targeting host RBPs that interact with SARS-CoV-2 RNA inhibit infection. Collectively, our results uncover a new universe of host-virus interactions with potential for new antiviral therapies against COVID-19.
Nucleic acid and histone modifications critically depend on the tricarboxylic acid (TCA) cycle for substrates and cofactors. Although a few TCA cycle enzymes have been reported in the nucleus, the corresponding pathways are considered to operate in mitochondria. Here, we show that a part of the TCA cycle is operational also in the nucleus. Using 13 C-tracer analysis, we identified activity of glutamine-to-fumarate, citrate-to-succinate, and glutamine-to-aspartate routes in the nuclei of HeLa cells. Proximity labeling mass spectrometry revealed a spatial vicinity of the involved enzymes with core nuclear proteins. We further show nuclear localization of aconitase 2 and 2-oxoglutarate dehydrogenase in mouse embryonic stem cells. Nuclear localization of the latter enzyme, which produces succinyl-CoA, changed from pluripotency to a differentiated state with accompanying changes in the nuclear protein succinylation. Together, our results demonstrate operation of an extended metabolic pathway in the nucleus, warranting a revision of the canonical view on metabolic compartmentalization.
We report vibrationally-resolved spectra of the S1 S0 transition of chlorobenzene using resonance-enhanced multiphoton ionization (REMPI) spectroscopy. We study chlorobenzene-h5 as well as its perdeuterated isotopologue, chlorobenzene-d5. Changes in the form of the vibrational modes between the isotopologues and also between the S0 and S1 electronic states are discussed for each species. Vibrational bands are assigned utilizing quantum chemical calculations, previous experimental results and isotopic shifts, including those between the 35 Cl and 37 Cl isotopologues. Previous work and assignments of the S1 spectra are discussed. Additionally, the vibrations in the ground state cation, D0 + , are considered, since these have also been used by previous workers in assigning the excited neutral state spectra.
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