Conformational Coupling Research Articles

Conformal hairy black holes of quartic quasi-topological gravity with power-Yang–Mills source

We study higher dimensional hairy black holes of quartic quasi-topological gravity in the framework of non-abelian power-Yang–Mills theory. It is shown that real solutions of the gravitational field equations exist only for positive values of quartic quasi-topological coefficient. Depending on the values of the mass, conformal coupling constants, quasi-topological coefficients, Yang–Mills magnetic charge, and nonlinearity parameter, they can be interpreted as black holes with one horizon, at most three horizons and naked singularity. It is also shown that the solution associated with these black holes has an essential curvature singularity at the centre r=0. Thermodynamic and conserved quantities for these hairy black holes are computed and we show that the first law has been verified. We also check thermodynamic stability in both canonical and grand canonical ensembles. In addition to this, we also formulate new power-Yang–Mills hairy black hole solutions in pure quasi-topological gravity. The physical and thermodynamic properties of these black holes are discussed as well. It is concluded that unlike Yang–Mills black holes without scalar hair there exist stability regions for the power-Yang–Mills hairy black holes in grand canonical ensemble. Finally, we discuss the thermodynamics of horizon flat power-Yang–Mills rotating black branes and analyze their thermodynamic and conserved quantities by using the counter-term method inspired by AdS/CFT correspondence.

Starobinsky inflation from string theory?

Starobinsky inflation is currently one of the best models concerning agreement with cosmological data. Despite this observational success, it is still lacking a robust embedding into a UV complete theory. Previous efforts to derive Starobinsky inflation from string theory have been based on the derivation of higher derivative curvature terms from the low-energy limit of ten-dimensional string theory. This approach is however known to fail due to the difficulty to tame the effect of contributions proportional to the Ricci scalar to a power larger than two. In this paper we investigate an alternative attempt which exploits instead the ubiquitous presence of scalar fields in string compactifications combined with the fact that Starobinsky inflation can be recast as Einstein gravity coupled to a scalar field with a precise potential and conformal coupling to matter fermions. After showing that the dilaton does not feature the right Yukawa coupling to matter, we focus in particular on type IIB Kähler moduli since they have shown to lead to exponential potentials with a Starobinsky-like plateau. We consider three classes of moduli with a different topological origin: the volume modulus, bulk fibre moduli, and blow-up modes. The only modulus with the correct coupling to matter is the volume mode but its potential does not feature any plateau at large field values. Fibre moduli admit instead a potential very similar to Starobinsky inflation with a natural suppression of higher curvature corrections, but they cannot reproduce the correct conformal coupling to matter. Blow-up modes have both a wrong potential and a wrong coupling. Our analysis implies therefore that embedding Starobinsky inflation into string theory seems rather hard. Finally, it provides a detailed derivation of the coupling to matter of fibre moduli which could be used as a way to discriminate Starobinsky from fibre inflation.

Mechanoresponsive Drug Release from a Flexible, Tissue-Adherent, Hybrid Hydrogel Actuator.

Soft robotic technologies for therapeutic biomedical applications require conformal and atraumatic tissue coupling that is amenable to dynamic loading for effective drug delivery or tissue stimulation. This intimate and sustained contact offers vast therapeutic opportunities for localized drug release. Herein, a new class of hybrid hydrogel actuator (HHA) that facilitates enhanced drug delivery is introduced. The multi-material soft actuator can elicit a tunable mechanoresponsive release of charged drug from its alginate/acrylamide hydrogel layer with temporal control. Dosing control parameters include actuation magnitude, frequency, and duration. The actuator can safely adhere to tissue via a flexible, drug-permeable adhesive bond that can withstand dynamic device actuation. Conformal adhesion of the hybrid hydrogel actuator to tissue leads to improved mechanoresponsive spatial delivery of the drug. Future integration of this hybrid hydrogel actuator with other soft robotic assistive technologies can enable a synergistic, multi-pronged treatment approach for the treatment of disease.

Response to Comment on “Inhibition mechanism of NKCC1 involves the carboxyl terminus and long-range conformational coupling”

Moseng et al. recently reported four cryo–electron microscopy structures of the human Na-K-2Cl cotransporter-1 (hNKCC1), both in the absence and presence of bound loop diuretic (furosemide or bumetanide). This research article included high-resolution structural information for a previously undefined structure of apo-hNKCC1 containing both the transmembrane and cytosolic carboxyl-terminal domains. The manuscript also demonstrated various conformational states of this cotransporter induced by diuretic drugs. On the basis of the structural information, the authors proposed a scissor-like inhibition mechanism that involves a coupled movement between the cytosolic and transmembrane domains of hNKCC1. This work has provided important insights into the mechanism of inhibition and substantiated the concept of a long-distance coupling involving movements of both the transmembrane and carboxyl-terminal cytoplasmic domains for inhibition.

Technical Comment on “Inhibition mechanism of NKCC1 involves the carboxyl terminus and long-range conformational coupling”

Flygaard, Habeck and Nissen question claims on bumetanide and furosemide binding to sodium-potassium-chloride cotransporter NKCC1.

A single-domain green fluorescent protein catenane

Natural proteins exhibit rich structural diversity based on the folds of an invariably linear chain. Macromolecular catenanes that cooperatively fold into a single domain do not belong to the current protein universe, and their design and synthesis open new territories in chemistry. Here, we report the design, synthesis, and properties of a single-domain green fluorescent protein catenane via rewiring the connectivity of GFP’s secondary motifs. The synthesis could be achieved in two steps via a pseudorotaxane intermediate or directly via expression in cellulo. Various proteins-of-interest may be inserted at the loop regions to give fusion protein catenanes where the two subunits exhibit enhanced thermal resilience, thermal stability, and mechanical stability due to strong conformational coupling. The strategy can be applied to other proteins with similar fold, giving rise to a family of single-domain fluorescent proteins. The results imply that there may be multiple protein topological variants with desirable functional traits beyond their corresponding linear protein counterparts, which are now made accessible and fully open for exploration.

Hierarchical Model of Weak Polyelectrolytes with Ionization and Conformation Consistency

Conventional models of weak polyelectrolytes are formulated in terms of either an average degree of ionization or a rigid polymer conformation. While the decoupling of segment-level ionization and polymer structure simplifies the theoretical procedure and is beneficial from a computational perspective, it misses intrachain correlations (i.e., interactions beyond adjacent monomers) that are important for systems at a low polymer concentration with strong electrostatic interactions. In this work, we propose a hierarchical method that incorporates the liquid-state theories with the site-binding model to account for the effects of the local ionic environment on both inter- and intrachain correlations. A wormlike-chain model is introduced to describe the coupling of polymer conformation and monomeric ionization with the long-range electrostatic interactions accounted for by using the Gibbs–Bogoliubov variational principle. Through an extensive comparison of the theoretical predictions with experimental titration curves for poly(acrylic acid) in different alkali chloride solutions, we demonstrate that the hierarchical model is able to quantify the charging behavior of weak polyelectrolytes over a broad range of solution conditions.

Measuring the ringdown scalar polarization of gravitational waves in Einstein-scalar-Gauss-Bonnet gravity

We model the scalar waves produced during the ringdown stage of binary black hole coalescence in Einstein scalar Gauss-Bonnet (EsGB) gravity, using numerical relativity simulations of the theory in the decoupling limit. Through a conformal coupling of the scalar field to the metric in the matter-field action, we show that the gravitational waves in this theory can have a scalar polarization. We model the scalar quasi-normal modes of the ringdown signal in EsGB gravity, and quantify the extent to which current and future gravitational wave detectors could observe the spectrum of scalar radiation emitted during the ringdown phase of binary black hole coalescence. We find that within the limits of the theory's coupling parameters set by current theoretical and observational constraints, the scalar ringdown signal from black hole remnants in the $10^1 - 10^3 \, M_{\odot}$ mass range is expected to be well below the detectability threshold with the current network of gravitational-wave detectors (LIGO-Virgo-KAGRA), but is potentially measurable with next-generation detectors such as the Einstein Telescope.

Coupling of conformation and CPD damage in nucleosomal DNA

UV-light can cause photodimerization and hence damages in DNA. Most frequent are cyclobutane pyrimidine dimer (CPD) damages, which predominantly form at TpT (thymine-thymine) steps. It is well known that CPD damage probability is different for single-stranded or double stranded DNA and depends on the sequence context. However, DNA deformation due to packing in nucleosomes can also influence CPD formation. Quantum mechanical calculations and Molecular Dynamics simulations indicate little CPD damage probability for DNA's equilibrium structure. We find that DNA needs to be deformed in a specific way to allow the HOMO → LUMO transition required for CPD damage formation. The simulation studies further show that the periodic CPD damage patterns measured in chromosomes and nucleosomes can be directly explained by the periodic deformation pattern of the DNA in the nucleosome complex. It supports previous findings on characteristic deformation patterns found in experimental nucleosome structures that relate to CPD damage formation. The result may have important implications for our understanding of UV-induced DNA mutations in human cancers.

Neutrino flavor oscillations inside matter in conformal coupling models

We recently studied neutrinos flavor oscillations in vacuum within conformal coupling models. In this paper, we extend that analysis by investigating neutrino flavor oscillations inside matter within a general conformal coupling scenario. We first derive the general formula for the flavor transition probability inside matter in arbitrary static and spherically symmetric spacetimes. The modified resonance formula of the MSW effect is derived and the corresponding adiabaticity parameter of the effect is extracted. An application of our results to the case of two-flavor neutrinos within the well-known chameleon and symmetron conformal coupling models is made.

Looking out for the Galileon in the nanohertz gravitational wave sky

We study the polarizations induced by the Galileon as a stochastic gravitational wave background in the cross correlated power in a pulsar timing array. Working within Galileon gravity, we first show that the scalar gravitational wave signature of the Galileon is encoded solely in its effective mass, which is controlled by the bare mass, conformal coupling, and a tadpole. Then, we study the phenomenology of the Galileon induced scalar polarizations and place observational constraints on these using the present NANOGrav data set. Our results feature longitudinal spatial correlation, indicative of a 10−22 eV subluminal Galileon, and show the Galileon polarizations as a statistically compelling source of the observed spatial correlation across millisecond pulsars, if there is any.

Stringent pulsar timing bounds on light scalar couplings to matter

Pulsar Timing constraints on scalar-tensor theories with conformal and disformal couplings to matter are discussed. Reducing the dynamics to the motion in the centre of mass frame and using the mean anomaly parametrisation, we find the first post-Newtonian corrections induced by the conformal and disformal interactions in the form of a generalized quasi-Keplerian solution. We also derive the radiation reaction force due to scalar radiation and the corresponding Post-Keplerian Parameters (PKP). We use different pulsar time of arrival (TOA) data sets to probe the scalar corrections to the PKP. In particular, we focus on systems with large orbital frequencies as the contributions to the PKP terms induced by the disformal coupling are sensitive to higher frequencies. We find that the most constraining { {pulsar timings}} are PSR B1913+16 and the double pulsar PSR J0737-3039A/B, being {{of the order of}} the Cassini bound on the conformal coupling obtained from the Shapiro effect in the solar system. { {The combined constraints using other pulsar timings give an upper bound on the conformal coupling $\beta^2 < 2.33 \cdot 10^{-5}$ and a lower bound on the disformal coupling scale of $\Lambda \geq 1.12 \ {\rm MeV}$ which is comparable to the Cassini bound and to the GW-170817 constraints respectively}}. Future measurements for pulsar timing with black hole companions are also discussed.

Molecular Dynamics Refinement of Open State Serotonin 5-HT3A Receptor Structures.

Pentameric ligand-gated ion channels play an important role in mediating fast neurotransmissions. As a member of this receptor family, cation-selective 5-HT3 receptors are a clinical target for treating nausea and vomiting associated with chemotherapy and radiation therapy (Thompson and Lummis, 2006). Multiple cryo-electron microscopy (cryo-EM) structures of 5-HT3 receptors have been determined in distinct functional states (e.g., open, closed, etc.) (Basak et al., 2018; Basak et al., 2018; Polovinkin et al., 2018; Zhang et al., 2015). However, recent work has shown that the transmembrane pores of the open 5-HT3 receptor structures rapidly collapse and become artificially asymmetric in molecular dynamics (MD) simulations. To avoid this hydrophobic collapse, Dämgen and Biggin developed an equilibration protocol that led to a stable open state structure of the glycine receptor in MD simulations (Dämgen and Biggin, 2020). However, the protocol failed to yield open-like structures of the 5-HT3 receptor in our simulations. Here, we present a refined equilibration protocol that involves the rearrangement of the transmembrane helices to achieve stable open state structures of the 5-HT3 receptor that allow both water and ion permeation through the channel. Notably, channel gating is mediated through collective movement of the transmembrane helices, involving not only pore lining M2 helices but also their cross-talk with the adjacent M1 and M3 helices. Thus, the successful application of our refined equilibration protocol underscores the importance of the conformational coupling between the transmembrane helices in stabilizing open-like structures of the 5-HT3 receptor.

Robustness of kinetic screening against matter coupling

We investigate neutron star solutions in scalar-tensor theories of gravity with first-order derivative self-interactions in the action and in the matter coupling. We assess the robustness of the kinetic screening mechanism present in these theories against general conformal couplings to matter. The latter include ones leading to the classical Damour-Esposito-Far\`ese scalarization, as well as ones depending on the kinetic term of the scalar field. We find that kinetic screening always prevails over scalarization, and that kinetic couplings with matter enhance the suppression of scalar gradients inside the star even more, without relying on the non-linear regime. Fine tuning the kinetic coupling with the derivative self-interactions in the action allows one to partially cancel the latter, resulting in a weakening of kinetic screening inside the star. This effect represents a novel way to break screening mechanisms inside matter sources, and provides new signatures that might be testable with astrophysical observations.

Lipid dependence of the conformational coupling across the membrane bilayer of full-length epidermal growth factor receptor.

Membrane proteins regulate several vital cellular processes, establishing them as major drug targets. A main function of membrane proteins is to transduce extracellular signal across the membrane bilayer. One such protein is the epidermal growth factor receptor (EGFR), which plays a crucial role in cell signaling and is implicated in cancer. While the structures of the extracellular and intracellular regions of this protein have been well-elucidated individually, conformational coupling connecting these two regions during signal transduction is challenging to probe due to the mixture of hydrophobic and hydrophilic domains intrinsic to membrane proteins. Here, I will discuss the signal transduction mechanism across full-length EGFR. We combine two biochemical tools, cell-free protein expression and nanodiscs, to isolate full-length, functional EGFR in a near-physiological environment. Using a multidisciplinary approach involving single-molecule Förster resonance energy transfer, mutagenesis, and molecular dynamics simulations, we observe a compaction in the intracellular domain of EGFR upon extracellular ligand binding in a neutral lipid environment. The ligand-induced extracellular/intracellular conformational coupling is reversed in the presence of anionic lipids, robust around the physiological 15-30% anionic content, and disappears in the presence of cholesterol. Our findings show how the extracellular and intracellular domains are coupled to each other in this critical receptor and the impact of the lipid composition in this conformational coupling. Our results could be universal to other membrane receptors which share the same structural homology and perform other significant functions.

Observing transmembrane conformational signaling with smFRET.

Transmembrane receptors transmit information about the local chemical environment across the membrane to regulate cellular signaling. The conformational changes responsible for signal transduction have been inaccessible due to the challenges associated with isolating and interrogating full-length receptors. As a result, studies have been limited to individual domains, where the transmembrane conformational dynamics are inherently missing. We overcame these limitations by embedding full-length receptors within membrane nanodiscs, a lipid bilayer encircled by a solubilizing belting protein, and using single-molecule Förster resonance energy transfer (FRET) to follow the transmembrane conformational changes through the receptor. First, in the aspartate chemoreceptor from E. coli we find a change in the cytoplasmic helical packing and dynamics upon ligand occupancy, which may be a general mechanism in coiled-coil signaling proteins. Second, in the mammalian epidermal growth factor receptor (EGFR), we identify a ligand- and lipid-dependent conformational change of the intracellular domain upon extracellular ligand binding, revealing a previously unknown transmembrane conformational coupling that, remarkably, is mediated by a single transmembrane alpha-helix.

Early dark energy and the screening mechanism

In the early Universe, dark energy may have a non-negligible contribution. If this dark energy corresponds to an early cosmological constant, it leads to a late-time huge dark energy density which is much larger than what is expected for the current expansion of the Universe. Using a conformal coupling of the quintessence to the dark matter, and based on the screening models, we propose a process to reduce the early dark energy to its ultimate value in the late time. Early and late time dark energies can be unified in a single component, in this way.

Detecting the Hydrogen Bond Cooperativity in a Protein β-Sheet by H/D Exchange

The hydrogen bond (H-bond) cooperativity in the β-sheet of GB3 is investigated by a NMR hydrogen/deuterium (H/D) exchange method. It is shown that the weakening of one backbone N-H…O=C H-bond between two β-strands, β1 and β2, due to the exchange of NH to ND of the H-bond donor in β1, perturbs the chemical shift of 13Cα, 13Cβ, 1Hα, 1HN, and 15N of the H-bond acceptor and its following residue in β2. Quantum mechanical calculations suggest that the -H-bond chemical shift isotope effect is caused by the structural reorganization in response to the H-bond weakening. This structural reorganization perturbs four neighboring H-bonds, with three being weaker and one being stronger, indicating that three H-bonds are cooperative and one is anticooperative with the perturbed H-bond. The sign of the cooperativity depends on the relative position of the H-bonds. This H-bond cooperativity, which contributes to β-sheet stability overall, can be important for conformational coupling across the β-sheet.

Inhibition mechanism of NKCC1 involves the carboxyl terminus and long-range conformational coupling.

The Na-K-2Cl cotransporter-1 (NKCC1) is an electroneutral Na+-dependent transporter responsible for simultaneously translocating Na+, K+, and Cl- ions into cells. In human tissue, NKCC1 plays a critical role in regulating cytoplasmic volume, fluid intake, chloride homeostasis, and cell polarity. Here, we report four structures of human NKCC1 (hNKCC1), both in the absence and presence of loop diuretic (bumetanide or furosemide), using single-particle cryo-electron microscopy. These structures allow us to directly observe various novel conformations of the hNKCC1 dimer. They also reveal two drug-binding sites located at the transmembrane and cytosolic carboxyl-terminal domains, respectively. Together, our findings enable us to delineate an inhibition mechanism that involves a coupled movement between the cytosolic and transmembrane domains of hNKCC1.

Comparison of allosteric signaling in DnaK and BiP using mutual information between simulated residue conformations.

The heat shock protein 70 kDa (Hsp70) chaperone system serves as a critical component of protein quality control across a wide range of prokaryotic and eukaryotic organisms. Divergent evolution and specialization to particular organelles have produced numerous Hsp70 variants which share similarities in structure and general function, but differ substantially in regulatory aspects, including conformational dynamics and activity modulation by cochaperones. The human Hsp70 variant BiP (also known as GRP78 or HSPA5) is of therapeutic interest in the context of cancer, neurodegenerative diseases, and viral infection, including for treatment of the pandemic virus SARS-CoV-2. Due to the complex conformational rearrangements and high sequential variance within the Hsp70 protein family, it is in many cases poorly understood which amino acid mutations are responsible for biochemical differences between protein variants. In this study, we predicted residues associated with conformational regulation of human BiP and Escherichia coli DnaK. Based on protein structure networks obtained from molecular dynamics simulations, we analyzed the shared information between interaction timelines to highlight residue positions with strong conformational coupling to their environment. Our predictions, which focus on the binding processes of the chaperone's substrate and cochaperones, indicate residues filling potential signaling roles specific to either DnaK or BiP. By combining predictions of individual residues into conformationally coupled chains connecting ligand binding sites, we predict a BiP specific secondary signaling pathway associated with substrate binding. Our study sheds light on mechanistic differences in signaling and regulation between Hsp70 variants, which provide insights relevant to therapeutic applications of these proteins.