Molecular interpretation of the LHCb pentaquarks from an analysis of J/ψp spectrum

A coupled-channel approach including the ΛcD¯(*) and ηcp channels in addition to the Σc(*)D¯(*) and J/ψp channels, as required by unitarity and heavy quark spin symmetry (HQSS), is applied to the hidden-charm pentaquark Pc states, i.e., Pc(4312), Pc(4440) and Pc(4457), discovered by LHCb Collaboration. It is demonstrated that to obtain cutoff independent results, the one-pion exchange potential in the multichannel systems is to be supplemented with next-leading order counter terms responsible for the S-wave-to-D-wave transitions. We show that the experimental data for the J/ψp mass distributions are fully in line with the ΣcD¯ and ΣcD¯* hadronic molecular interpretation of the Pc(4312) and Pc(4440)/Pc(4457), respectively. A narrow Σc*D¯ molecule around 4.38 GeV is required by the HQSS with the evidence for its existence seen in the J/ψp spectrum. Moreover, we predict the line shapes for the elastic and inelastic channels.

Molecular features underlying differential SHP1/SHP2 binding of immune checkpoint receptors

A large number of inhibitory receptors recruit SHP1 and/or SHP2, tandem-SH2-containing phosphatases, through phosphotyrosine-based motifs ITIM and ITSM. Despite the similarity, these receptors exhibit differential effector binding specificities, as exemplified by the immune checkpoint receptors PD-1 and BTLA, which preferentially recruit SHP2 and SHP1 respectively. The molecular basis by which structurally similar receptors discriminate SHP1 and SHP2 is unclear. Here, we provide evidence that human PD-1 and BTLA optimally bind to SHP1 and SHP2 via a bivalent, parallel mode that involves both SH2 domains of SHP1 or SHP2. PD-1 mainly uses its ITSM to prefer SHP2 over SHP1 via their C-terminal SH2 domains (cSH2): swapping SHP1-cSH2 with SHP2-cSH2 enabled PD-1:SHP1 association in T cells. In contrast, BTLA primarily utilizes its ITIM to prefer SHP1 over SHP2 via their N-terminal SH2 domains (nSH2). The ITIM of PD-1, however, appeared to be de-emphasized due to a glycine at pY+1 position. Substitution of this glycine with alanine, a residue conserved in BTLA and several SHP1-recruiting receptors, was sufficient to induce PD-1:SHP1 interaction in T cells. Finally, structural simulation and mutagenesis screening showed that SHP1 recruitment activity exhibits a bell-shaped dependence on the side chain volume of the pY+1 residue of ITIM. Collectively, we provide a molecular interpretation of the SHP1/SHP2-binding specificities of PD-1 and BTLA, with implications for the mechanisms of a large family of therapeutically relevant receptors.

An atomistic view on liquid phase adsorption

The effect of immobilized β-cyclodextrin (bCD) molecules inside a mesoporous silica support on the uptake of benzene and p-nitrophenol from aqueous solution was investigated using all-atom molecular dynamics (MD) simulations. The calculated adsorption isotherms are discussed with respect to the free energies of binding for a 1:1 complex of bCD and the aromatic guest molecule. The adsorption capacity of the bCDcontaining material significantly exceeds the amount corresponding to a 1:1 binding scenario, in agreement with experimental observations for benzene adsorption. The demonstrated feasibility of classical all-atom MD simulations to calculate liquid phase adsorption isotherms paves the way to a molecular interpretation of experimental data that are too complex to be described by empirical models.

Conditional Cooperativity in DNA Minor-Groove Recognition by Oligopeptides

The recognition of specific DNA sequences in processes such as transcription is associated with a cooperative binding of proteins. Some transcription regulation mechanisms involve additional proteins that can influence the binding cooperativity by acting as corepressors or coactivators. In a conditional cooperativity mechanism, the same protein can induce binding cooperativity at one concentration and inhibit it at another. Here, we use calorimetric (ITC) and spectroscopic (UV, CD) experiments to show that such conditional cooperativity can also be achieved by the small DNA-directed oligopeptides distamycin and netropsin. Using a global thermodynamic analysis of the observed binding and (un)folding processes, we calculate the phase diagrams for this system, which show that distamycin binding cooperativity is more pronounced at lower temperatures and can be first induced and then reduced by increasing the netropsin or/and Na+ ion concentration. A molecular interpretation of this phenomenon is suggested.

Potential Crucial Role of COX-1 and/or COX-2 Inhibition, NSAIDs or Aspirin Triggered Lipoxins and Resolvins in Amelioration of COVID-19 Mortality

Aspirin has been recently suggested to be independently associated with reduced risk of mechanical ventilation, ICU admission and in-hospital mortality of COVID-19. However, we claim that the molecular interpretation of these important results was not scientifically valid, and we provide our academic interpretation that is also basing on our real-life practice using non-steroidal anti-inflammatory drugs in management of COVID-19 and we suggest that inhibition of COX-1 and/or COX-2 enzymes might play a lifesaving role in COVID-19 management, and we further discuss the potential of aspirin triggered lipoxins and resolivns in the same context.

X(6200) as a compact tetraquark in the QCD string model

Recently the LHCb Collaboration announced the first observation of nontrivial structures in the double-$$J/\psi $$ J / ψ mass spectrum in the mass range 6.2–7.2 GeV, and a theoretical coupled-channel analysis of these data performed in Dong et al. (Phys Rev Lett 126:132001, 2021) evidenced the existence of a new state X(6200) close to the double-$$J/\psi $$ J / ψ threshold. Although its molecular interpretation seems the most plausible assumption, the present data do not exclude an admixture of a compact component in its wave function, for which a fully-charmed compact tetraquark is the most natural candidate. It is argued in this work that the QCD string model is compatible with the existence of a compact $$cc{\bar{c}}{\bar{c}}$$ c c c ¯ c ¯ state bound by QCD forces just below the double-$$J/\psi $$ J / ψ threshold. A nontrivial interplay of the quark dynamics associated with this compact state and the molecular dynamics provided by soft gluon exchanges between $$J/\psi $$ J / ψ mesons is discussed and the physical X(6200) is argued to be a shallow bound state, in agreement with the results of the aforementioned coupled-channel analysis of the LHCb data.

LeMeDISCO: A computational method for large-scale prediction & molecular interpretation of disease comorbidity

Often different diseases tend to co-occur (i.e., they are comorbid), which yields the question: what is the molecular basis of their coincidence? Perhaps, common proteins are comorbid disease drivers. To understand the origin of disease comorbidity and to identify the essential proteins and pathways underlying comorbid diseases, we developed LeMeDISCO (Large-Scale Molecular Interpretation of Disease Comorbidity), an algorithm that predicts disease comorbidities from shared mode of action (MOA) proteins predicted by the AI-based MEDICASCY algorithm. LeMeDISCO was applied to predict the general occurrence of comorbid diseases for 3608 distinct diseases. To illustrate the power of LeMeDISCO, we elucidate the possible etiology of coronary artery disease and ovarian cancer by determining the comorbidity enriched MOA proteins and pathways and suggest hypotheses for subsequent scientific investigation. The LeMeDISCO web server is available for academic users at: http://sites.gatech.edu/cssb/LeMeDISCO.

Molecular Features Underlying Shp1/Shp2 Discrimination by Immune Checkpoint Receptors

Numerous inhibitory immunoreceptors operate by recruiting phosphatase effectors Shp1 and Shp2 through conserved motifs ITIM and ITSM. Despite the similarity, these receptors exhibit distinct effector binding specificities, as exemplified by PD-1 and BTLA, which preferentially recruit Shp2 and Shp1 respectively. The molecular basis of Shp1/Shp2 discrimination is unclear. Here, we provide evidence that optimal PD-1 and BTLA binding to both Shp1 and Shp2 occurs via a bivalent, parallel mode that involves both SH2 domains of Shp1/Shp2. Moreover, PD-1 mainly uses its ITSM to discriminate Shp2 from Shp1 via their C-terminal SH2 domains. Supportive of this model, swapping the Shp1-cSH2 with Shp2-cSH2 enabled PD-1:Shp1 association in T cells. In contrast, BTLA primarily utilizes its ITIM to discriminate Shp1 from Shp2 via their N-terminal SH2 domains. Substitution of glycine at pY+1 position of the PD-1-ITIM with alanine, a residue conserved in several Shp1-recruiting receptors, was sufficient to induce PD-1:Shp1 interaction in T cells. Finally, mutagenesis screening shows that Shp1 recruitment exhibits a bell-shaped dependence on the side chain volume of the pY+1 residue of ITIM. Collectively, we provide a molecular interpretation of the Shp1/Shp2-binding specificities of PD-1 and BTLA, with general implications for the mechanism of effector discrimination by inhibitory receptors.

The potential crucial role of COX-1 inhibition and/or Aspirin triggered lipoxins and resolvins in amelioration of COVID-19 mortality

Aspirin has been recently suggested to be independently associated with reduced risk of mechanical ventilation, ICU admission and in-hospital mortality of COVID-19. However, we claim that the molecular interpretation of these important results was not scientifically valid and we provide our academic interpretation that is also basing on our real-life practice using non-steroidal anti-inflammatory drugs in management of COVID-19 and we suggest that inhibition of COX-1 and/or COX-2 enzymes might play a life saving role in COVID-19 management and we further discuss the potential of aspirin triggered lipoxins and resolivns in the same context.

Hyperpolarizability of Water at the Air-Vapor Interface: Numerical Modeling Questions Standard Experimental Approximations

<div>In this article, we investigate the molecular first hyperpolarizability of water molecules nearby the liquid-vapor interface. The hyperpolarizability of each molecule is calculated at the quantum level within an explicit, inhomogeneous electrostatic embedding. We report that the average molecular first hyperpolarizability tensor depends on the distance relative to the interface, but it practically respects the Kleinman symmetry everywhere in the liquid. </div><div>Within this numerical approach, based on the dipolar approximation, the water layer contributing to the Surface Second Harmonic Generation (S-SHG) intensity is less than a nanometer. We show that within this interfacial layer, the common assumption considering a single, constant hyperpolarizability for all water molecules is not supported by our data: hyperpolarizability fluctuations are expected to impact the S-SHG intensity. These results represent a step forward the molecular interpretation of experimental S-SHG signal of aqueous interfaces. </div>