The universal expression for the amplitude square in quantum electrodynamics

The universal expression for the amplitude square |u_f M u_i|^2 for any matrix of interaction M is derived. It has obvious covariant form. It allows the avoidance of calculation of products of the Dirac's matrices traces and allows easy calculation of cross-sections of any different processes with polarized and unpolarized particles.Comment: 4 page

Data-driven derivation of molecular substructures that enhance drug activity in Gram-negative bacteria

[Image: see text] The complex cell envelope of Gram-negative bacteria creates a formidable barrier to antibiotic influx. Reduced drug uptake impedes drug development and contributes to a wide range of drug-resistant bacterial infections, including those caused by extremely resistant species prioritized by the World Health Organization. To develop new and efficient treatments, a better understanding of the molecular features governing Gram-negative permeability is essential. Here, we present a data-driven approach, using matched molecular pair analysis and machine learning on minimal inhibitory concentration data from Gram-positive and Gram-negative bacteria to uncover chemical features that influence Gram-negative bioactivity. We find recurring chemical moieties, of a wider range than previously known, that consistently improve activity and suggest that this insight can be used to optimize compounds for increased Gram-negative uptake. Our findings may help to expand the chemical space of broad-spectrum antibiotics and aid the search for new antibiotic compound classes

A cooperative knock-on mechanism underpins Ca2+-selective cation permeation in TRPV channels

The selective exchange of ions across cellular membranes is a vital biological process. Ca2+-mediated signaling is implicated in a broad array of physiological processes in cells, while elevated intracellular concentrations of Ca2+ are cytotoxic. Due to the significance of this cation, strict Ca2+ concentration gradients are maintained across the plasma and organelle membranes. Therefore, Ca2+ signaling relies on permeation through selective ion channels that control the flux of Ca2+ ions. A key family of Ca2+-permeable membrane channels is the polymodal signal-detecting transient receptor potential (TRP) ion channels. TRP channels are activated by a wide variety of cues including temperature, small molecules, transmembrane voltage, and mechanical stimuli. While most members of this family permeate a broad range of cations non-selectively, TRPV5 and TRPV6 are unique due to their strong Ca2+ selectivity. Here, we address the question of how some members of the TRPV subfamily show a high degree of Ca2+ selectivity while others conduct a wider spectrum of cations. We present results from all-atom molecular dynamics simulations of ion permeation through two Ca2+-selective and two non-selective TRPV channels. Using a new method to quantify permeation cooperativity based on mutual information, we show that Ca2+-selective TRPV channel permeation occurs by a three-binding site knock-on mechanism, whereas a two-binding site knock-on mechanism is observed in non-selective TRPV channels. Each of the ion binding sites involved displayed greater affinity for Ca2+ over Na+. As such, our results suggest that coupling to an extra binding site in the Ca2+-selective TRPV channels underpins their increased selectivity for Ca2+ over Na+ ions. Furthermore, analysis of all available TRPV channel structures shows that the selectivity filter entrance region is wider for the non-selective TRPV channels, slightly destabilizing ion binding at this site, which is likely to underlie mechanistic decoupling.</p

On the ion coupling mechanism of the MATE transporter ClbM

Bacteria use a number of mechanisms to defend themselves from antimicrobial drugs. One important defense strategy is the ability to export drugs by multidrug transporters. One class of multidrug transporter, the so-called multidrug and toxic compound extrusion (MATE) transporters, extrude a variety of antibiotic compounds from the bacterial cytoplasm. These MATE transporters are driven by a Na+, H+, or combined Na+/H+ gradient, and act as antiporters to drive a conformational change in the transporter from the outward to the inward-facing conformation. In the inward-facing conformation, a chemical compound (drug) binds to the protein, resulting in a switch to the opposite conformation, thereby extruding the drug. Using molecular dynamics simulations, we now report the structural basis for Na+ and H+ binding in the dual ion coupled MATE transporter ClbM from Escherichia coli, which is connected to colibactin-induced genotoxicity, yielding novel insights into the ion/drug translocation mechanism of this bacterial transporter.</p

A role for loop G in the β1 strand in GABA_A receptor activation

The GABAA receptor α subunit β1 strand runs anti-parallel to the β2 strand, which contains loop D, known to participate in receptor activation and agonist binding. However, a role for the β1 strand has yet to be established. We used molecular dynamics simulation to quantify the solvent accessible surface area (SASA) of β1 strand residues in the GABAA β3 homopentamer structure. Residues in the complementary interface equivalent to those between Asp43 and Thr47 in the a1 subunit have an alternating pattern of high and low SASA consistent with a β strand structure. We investigated the functional role of these β1 strand residues in the α1 subunit by individually replacing them with Cys residues. D43C and T47C substitutions reduced the apparent potency of GABA at α1β2γ2 receptors by around 50-fold and 8-fold, respectively, whereas the F45C substitution caused a biphasic GABA concentration-response relationship and increased spontaneous gating. Receptors with D43C or T47C substitutions were sensitive to MTSEA modification. However, GABA-evoked currents mediated by α1(F45C)β2γ2 receptors were unaffected by MTSEA, suggesting that this residue is inaccessible. Both GABA and the allosteric agonist propofol reduced MTSEA modification of α1(D43C)β2γ2 and α1(T47C)β2γ2 receptors indicating movement of the β1 strand even during allosteric activation. This is in contrast to α1(F64C)β2γ2 receptors where only GABA, but not propofol reduced MTSEA modification. These findings provide the first functional evidence for movement of the β1 strand during gating of the receptor and identify residues that are critical for maintaining GABAA receptor function. This article is protected by copyright. All rights reserved.</p

The lipid environment determines the activity of the Escherichia coli ammonium transporter AmtB

The movement of ammonium across biologic membranes is a fundamental process in all living organ-isms and is mediated by the ubiquitous ammonium transporter/methylammonium permease/rhesus protein (Amt/Mep/Rh) family of transporters. Recent structural analysis and coupled mass spectrometry studies have shown that the Escherichia coli ammonium transporter AmtB specifically binds 1-palmitoyl-2-oleoyl phosphatidylglycerol (POPG). Upon POPG binding, several residues of AmtB undergo a small conformational change, which stabilizes the protein against unfolding. However, no studies have so far been conducted, to our knowledge, to explore whether POPG binding to AmtB has functional consequences. Here, we used an in vitro experimental assay with purified components, together with molecular dynamics simulations, to characterize the relation between POPG binding and AmtB activity. We show that the AmtB activity is electrogenic. Our results indicate that the activity, at the molecular level, of Amt in archaebacteria and eubacteria may differ. We also show that POPG is an important cofactor for AmtB activity and that, in the absence of POPG, AmtB cannot complete the full translocation cycle. Furthermore, our simulations reveal previously undiscovered POPG binding sites on the intracellular side of the lipid bilayer between the AmtB subunits. Possible molecular mechanisms explaining the functional role of POPG are discussed

Accurate prediction of dynamic protein-ligand binding using P-score ranking

Protein–ligand binding prediction typically relies on docking methodologies and associated scoring functions to propose the binding mode of a ligand in a biological target. Significant challenges are associated with this approach, including the flexibility of the protein–ligand system, solvent-mediated interactions, and associated entropy changes. In addition, scoring functions are only weakly accurate due to the short time required for calculating enthalpic and entropic binding interactions. The workflow described here attempts to address these limitations by combining supervised molecular dynamics with dynamical averaging quantum mechanics fragment molecular orbital. This combination significantly increased the ability to predict the experimental binding structure of protein–ligand complexes independent from the starting position of the ligands or the binding site conformation. We found that the predictive power could be enhanced by combining the residence time and interaction energies as descriptors in a novel scoring function named the P-score. This is illustrated using six different protein–ligand targets as case studies.</p

Accurate prediction of dynamic protein-ligand binding using P-score ranking

Protein–ligand binding prediction typically relies on docking methodologies and associated scoring functions to propose the binding mode of a ligand in a biological target. Significant challenges are associated with this approach, including the flexibility of the protein–ligand system, solvent-mediated interactions, and associated entropy changes. In addition, scoring functions are only weakly accurate due to the short time required for calculating enthalpic and entropic binding interactions. The workflow described here attempts to address these limitations by combining supervised molecular dynamics with dynamical averaging quantum mechanics fragment molecular orbital. This combination significantly increased the ability to predict the experimental binding structure of protein–ligand complexes independent from the starting position of the ligands or the binding site conformation. We found that the predictive power could be enhanced by combining the residence time and interaction energies as descriptors in a novel scoring function named the P-score. This is illustrated using six different protein–ligand targets as case studies.</p