Conformational Coupling Research Articles

Effects of Ortho-Phenyl Substitution on the rISC Rate of D–A Type TADF Molecules

Two new donor (D)–acceptor (A) type molecules, PXZ-DBTO2 and PXZ-Ph-DBTO2, configured with phenoxazine donor and dibenzothiophene-S,S-dioxide acceptor are reported. PXZ-Ph-DBTO2, with a phenyl group introduced at the ortho position of PXZ, was used to probe the effects of the congested aryl substitution on the molecular conformation and electronic coupling toward the acceptor core, as well as the thermally activated delayed fluorescence behavior. The highly twisted donor–acceptor configurations of these two molecules were confirmed by X-ray analysis. Different D–A conformations stemmed from the steric interactions between the phenyl group and acceptor core, which leads the nitrogen lone pair electrons of the PXZ-Ph-DBTO2 donor to conjugate across the D–A bridge, whereas in PXZ-DBTO2 the lone pairs remain localized on the donor and strongly mix with the donor π electrons. However, both PXZ-Ph-DBTO2 and PXZ-DBTO2 have the same energy splitting between the charge-transfer states and local donor triplet state...

Non-conformal holographic Gauss-Bonnet hydrodynamics

We study hydrodynamics of four-dimensional non-conformal holographic plasma with non-equal central charges c ≠ a at the ultraviolet fixed point. We compute equation of state, the speed of sound waves, transport coefficients (shear and bulk viscosities), and discuss causality. We study the asymptotic character of the hydrodynamic series for the homogeneous and isotropic expansion of the plasma. We perform computations for finite c − a ≠ 0, but to leading nonvanishing order in the conformal symmetry breaking coupling.

Electrohydrodynamics in nanochannels coated by mixed polymer brushes: effects of electric field strength and solvent quality

We examine the electrohydrodynamics in mixed polymer brush-coated nanochannels and the conformational dynamics of grafted polymers using molecular dynamics simulations. Charged (A) and neutral polymers (B) are alternately grafted on the channel surfaces. The effects of the electric field strength and solvent quality are addressed in detail. The dependence of electroosmotic flow characteristics and polymer conformational behavior on the solvent quality is influenced due to the change of the electric field strength. The enhanced electric field induces a collapse of the neutral polymer chains which adopt a highly extended conformation along the flow direction. However, the thickness of the charged polymer layer is affected weakly by the electric field, and even a slight swelling is identified for the A–B attraction case, implying the conformational coupling between two polymer species. Furthermore, the charged polymer chains incline entirely towards the electric field direction oppositely to the flow direction. More importantly, unlike the neutral polymer chains, the shape factor of the charged polymer chains, which is used to describe the overall shape of polymer chains, is reduced significantly with increasing the electric field strength, corresponding to a more coiled structure.

Conformational Coupling and trans-Inhibition in the Human Antigen Transporter Ortholog TmrAB Resolved with Dipolar EPR Spectroscopy.

ATP-binding cassette (ABC) exporters actively move chemically diverse substrates across biological membranes. Their malfunction leads to human diseases. Many ABC exporters encompass asymmetric nucleotide-binding sites (NBSs), and some of them are inhibited by the transported substrate. The functional relevance of the catalytic asymmetry or the mechanism for trans-inhibition remains elusive. Here, we investigated TmrAB, a functional homologue of the human antigen translocation complex TAP using advanced electron-electron double resonance spectroscopy. In the presence of ATP, the heterodimeric ABC exporter exists in a tunable equilibrium between inward- and outward-facing conformations. The two NBSs exhibit pronounced asymmetry in the open-to-close equilibrium. The closed conformation is more favored at the degenerate NBS, and closure of either of the NBS is sufficient to open the extracellular gate. We define the mechanistic basis for trans-inhibition, which operates by a reverse transition from the outward-facing state through an occluded conformation. These novel findings uncover the central role of reversible conformational equilibrium in the function and regulation of an ABC exporter and establish a mechanistic framework for future investigations on other medically important transporters with imprinted asymmetry. Also, this study demonstrates for the first-time the feasibility to resolve equilibrium populations at multiple domains and their interdependence for global conformational changes in a large membrane protein complex.

Searching for dark matter-dark energy interactions: Going beyond the conformal case

We consider a generic cosmological model which allows for non-gravitational direct couplings between dark matter and dark energy. The distinguishing cosmological features of these couplings can be probed by current cosmological observations, thus enabling us to place constraints on this generic interaction which is composed of the conformal and disformal coupling functions. We perform a global analysis in order to independently constrain the conformal, disformal, and mixed interactions between dark matter and dark energy by combining current data from: Planck observations of the cosmic microwave background radiation anisotropies, a combination of measurements of baryon acoustic oscillations, a supernovae Type Ia sample, a compilation of Hubble parameter measurements estimated from the cosmic chronometers approach, direct measurements of the expansion rate of the Universe today, and a compilation of growth of structure measurements. We find that in these coupled dark energy models, the influence of the local value of the Hubble constant does not significantly alter the inferred constraints when we consider joint analyses that include all cosmological probes. Moreover, the parameter constraints are remarkably improved with the inclusion of the growth of structure data set measurements. We find no compelling evidence for an interaction within the dark sector of the Universe.

Low-frequency analogue Hawking radiation: The Bogoliubov-de Gennes model

We analytically study the low-frequency properties of the analogue Hawking effect in Bose-Einstein condensates. We show that in one-dimensional flows displaying an analogue horizon, the Hawking effect is dominant in the low-frequency regime. This happens despite non vanishing greybody factors, that is, the coupling of the Hawking mode and its partner to the mode propagating with the flow. To show this, we obtained analytical expressions for the scattering coefficients, in general flows and taking into account the full Bogoliubov dispersion relation. We discuss the obtained expressions for the greybody factors. In particular, we show that they can be significantly decreased if the flow obeys a conformal coupling condition. We argue that in the presence of a small but non-zero temperature, reducing greybody factors greatly facilitates the observation of entanglement, that is, establishing that the state of the Hawking mode and its partner is non-separable.

The architectures of iterative type I PKS and FAS.

Covering: up to mid of 2018 Type I fatty acid synthases (FASs) are giant multienzymes catalyzing all steps of the biosynthesis of fatty acids from acetyl- and malonyl-CoA by iterative precursor extension. Two strikingly different architectures of FAS evolved in yeast (as well as in other fungi and some bacteria) and metazoans. Yeast-type FAS (yFAS) assembles into a barrel-shaped structure of more than 2 MDa molecular weight. Catalytic domains of yFAS are embedded in an extensive scaffolding matrix and arranged around two enclosed reaction chambers. Metazoan FAS (mFAS) is a 540 kDa X-shaped dimer, with lateral reaction clefts, minimal scaffolding and pronounced conformational variability. All naturally occurring yFAS are strictly specialized for the production of saturated fatty acids. The yFAS architecture is not used for the biosynthesis of any other secondary metabolite. On the contrary, mFAS is related at the domain organization level to major classes of polyketide synthases (PKSs). PKSs produce a variety of complex and potent secondary metabolites; they either act iteratively (iPKS), or are linked via directed substrate transfer into modular assembly lines (modPKSs). Here, we review the architectures of yFAS, mFAS, and iPKSs. We rationalize the evolution of the yFAS assembly, and provide examples for re-engineering of yFAS. Recent studies have provided novel insights into the organization of iPKS. A hybrid crystallographic model of a mycocerosic acid synthase-like Pks5 yielded a comprehensive visualization of the organization and dynamics of fully-reducing iPKS. Deconstruction experiments, structural and functional studies of specialized enzymatic domains, such as the product template (PT) and the starter-unit acyltransferase (SAT) domain have revealed functional principles of non-reducing iterative PKS (NR-PKSs). Most recently, a six-domain loading region of an NR-PKS has been visualized at high-resolution together with cryo-EM studies of a trapped loading intermediate. Altogether, these data reveal the related, yet divergent architectures of mFAS, iPKS and also modPKSs. The new insights highlight extensive dynamics, and conformational coupling as key features of mFAS and iPKS and are an important step towards collection of a comprehensive series of snapshots of PKS action.

Subunit Capture Mechanics in Calcium Calmodulin Dependent Kinase II

Molecular dynamics simulations examined how single transphosphorylation between adjacent subunits of calcium calmodulin dependent protein kinase II (CaMKII) effects conformational coupling. One (receiver) kinase captures and phosphorylates the regulatory domain of a donor kinase forming a chained dimer. Identified substrate binding sequences formed nodes in long-range, parallel signal relays linking regulatory peptides in adjacent subunits. Monomer subunit architecture was co-opted in the auto-phosphorylating dimer but the community hub shifted from the nucleotide binding pocket to a hydrophobic cluster between the captured peptide and a key helix in its binding pocket. Phosphorylation of this peptide modulated the dielectric of the pocket to reduce helix flexibility and collective motions of the receiver kinase domain. The signal relay was strengthened with phosphorylationdependent conformational transitions completed within hundred nanoseconds. The network couplings should guide allosteric inhibitor design. Chained dimers, in addition to intra-holoenzyme spread, may facilitate exchange between holoenzymes to prolong activated population lifetimes.

Dark Energy after GW170817 and GRB170817A.

The observation of GW170817 and its electromagnetic counterpart implies that gravitational waves travel at the speed of light, with deviations smaller than a few×10^{-15}. We discuss the consequences of this experimental result for models of dark energy and modified gravity characterized by a single scalar degree of freedom. To avoid tuning, the speed of gravitational waves must be unaffected not only for our particular cosmological solution but also for nearby solutions obtained by slightly changing the matter abundance. For this to happen, the coefficients of various operators must satisfy precise relations that we discuss both in the language of the effective field theory of dark energy and in the covariant one, for Horndeski, beyond Horndeski, and degenerate higher-order theories. The simplification is dramatic: of the three functions describing quartic and quintic beyond Horndeski theories, only one remains and reduces to a standard conformal coupling to the Ricci scalar for Horndeski theories. We show that the deduced relations among operators do not introduce further tuning of the models, since they are stable under quantum corrections.

De novo reconstitution reveals the proteins required for skeletal muscle voltage-induced Ca2+ release

Skeletal muscle contraction is triggered by Ca2+ release from the sarcoplasmic reticulum (SR) in response to plasma membrane (PM) excitation. In vertebrates, this depends on activation of the RyR1 Ca2+ pore in the SR, under control of conformational changes of CaV1.1, located ∼12 nm away in the PM. Over the last ∼30 y, gene knockouts have revealed that CaV1.1/RyR1 coupling requires additional proteins, but leave open the possibility that currently untested proteins are also necessary. Here, we demonstrate the reconstitution of conformational coupling in tsA201 cells by expression of CaV1.1, β1a, Stac3, RyR1, and junctophilin2. As in muscle, depolarization evokes Ca2+ transients independent of external Ca2+ entry and having amplitude with a saturating dependence on voltage. Moreover, freeze-fracture electron microscopy indicates that the five identified proteins are sufficient to establish physical links between CaV1.1 and RyR1. Thus, these proteins constitute the key elements essential for excitation-contraction coupling in skeletal muscle.

PDZ Ligand Binding-Induced Conformational Coupling of the PDZ–SH3–GK Tandems in PSD-95 Family MAGUKs

Discs large (DLG) MAGUKs are abundantly expressed in glutamatergic synapses, crucial for synaptic transmission, and plasticity by anchoring various postsynaptic components including glutamate receptors, downstream scaffold proteins and signaling enzymes. Different DLG members have shared structures and functions, but also contain unique features. How DLG family proteins function individually and cooperatively is largely unknown. Here, we report that PSD-95 PDZ3 directly couples with SH3–GK tandem in a PDZ ligand binding-dependent manner, and the coupling can promote PSD-95 dimerization and multimerization. Aided by sortase-mediated protein ligation and selectively labeling, we elucidated the PDZ3/SH3–GK conformational coupling mechanism using NMR spectroscopy. We further demonstrated that PSD-93, but not SAP102, can also undergo PDZ3 ligand binding-induced conformational coupling with SH3–GK and form homo-oligomers. Interestingly, PSD-95 and PSD-93 can also form ligand binding-induced hetero-oligomers, suggesting a cooperative assembly mechanism for the mega-N-methyl-d-aspartate receptor synaptic signaling complex. Finally, we provide evidence showing that ligand binding-induced conformational coupling between PDZ and SH3–GK is a common feature for other MAGUKs including CASK and PALS1.

Motions of the SecA protein motor bound to signal peptide: Insights from molecular dynamics simulations

SecA is an essential part of the Sec pathway for protein secretion in bacteria. In this pathway, SecA interacts with the N-terminal fragment of the secretory protein – the signal peptide, and couples binding and hydrolysis of adenosine triphosphate with movement of the secretory protein across the SecY protein translocon. How interactions with the signal peptide alter the conformational dynamics and long-distance conformational couplings of SecA is a key open question that we address here with molecular dynamics techniques. Analyses of protein motions indicate that the signal peptide alters SecA dynamics not only at the site where this peptide binds, but also at a nucleotide-binding domain. Hydrogen bond clusters contribute to the long-distance propagation of changes in SecA dynamics.

D-brane disformal coupling and thermal dark matter

Conformal and Disformal couplings between a scalar field and matter occur naturally in general scalar-tensor theories. In D-brane models of cosmology and particle physics, these couplings originate from the D-brane action describing the dynamics of its transverse (the scalar) and longitudinal (matter) fluctuations, which are thus coupled. During the post-inflationary regime and before the onset of big-bang nucleosynthesis (BBN), these couplings can modify the expansion rate felt by matter, changing the predictions for the thermal relic abundance of dark matter particles and thus the annihilation rate required to satisfy the dark matter content today. We study the D-brane-like conformal and disformal couplings effect on the expansion rate of the universe prior to BBN and its impact on the dark matter relic abundance and annihilation rate. For a purely disformal coupling, the expansion rate is always enhanced with respect to the standard one. This gives rise to larger cross-sections when compared to the standard thermal prediction for a range of dark matter masses, which will be probed by future experiments. In a D-brane-like scenario, the scale at which the expansion rate enhancement occurs depends on the string coupling and the string scale.

One loop corrected conformally coupled scalar mode equations during inflation

We employ a fully renormalized computation of the one loop contribution to the self-mass-squared of the conformally coupled (CC) scalar interacting with gravitons during inflation to study how inflationary produced gravitons affect the CC scalar evolution equation. The quantum corrected scalar mode functions turn out to get a secular growth effect, proportional to a logarithm of the scale factor at late times.

Hoisting-Loop in Bacterial Multidrug Exporter AcrB Is a Highly Flexible Hinge That Enables the Large Motion of the Subdomains.

The overexpression of RND-type exporters is one of the main causes of multidrug resistance (MDR) in Gram-negative pathogens. In RND transporters, such as Escherichia coli's main efflux pump AcrB, drug efflux occurs in the porter domain, while protons flow through the transmembrane domain: remote conformational coupling. At the border of a transmembrane helix (TM8) and subdomain PC2, there is a loop which makes a hoisting movement by a random-coil-to-α-helix change, and opens and closes a drug channel entrance. This loop is supposed to play a key role in the allosteric conformational coupling between the transmembrane and porter domain. Here we show the results of a series of flexibility loop-mutants of AcrB. We determined the crystal structure of a three amino acid truncated loop mutant, which is still a functional transporter, and show that the short α-helix between Cβ15 and the loop unwinds to a random coil in the access and binding monomers and in the extrusion monomer it makes a partially stretched coil-to-helix change. The loop has undergone compensatory conformational changes and still facilitates the opening and closing of the channel. In addition, more flexible mutated loops (proline mutated and significantly elongated) can still function during export. The flexibility in this region is however limited, as an even more truncated mutant (six amino acid deletion) becomes mostly inactive. We found that the hoisting-loop is a highly flexible hinge that enables the conformational energy transmission passively.

Spacetime anisotropy affects cosmological entanglement

Most existing cosmological entanglement studies are focused on the isotropic Robertson–Walker (RW) spacetime. Here we go beyond this limitation and study the influence of anisotropy on entanglement generated by dynamical spacetime. Since the isotropic spacetime is viewed as a background medium and the anisotropy is incorporated as perturbation, we decompose entanglement entropy into isotropic and anisotropic contributions. The latter is shown to be non-negligible by analyzing two cosmological models with weak and conformal coupling. We also show the possibility of using entanglement to infer about universe features.

Creation of mass dimension one fermionic particles in asymptotically expanding universe

In the present work we study the process of particle creation for mass dimension one fermionic fields (sometimes named Elko) as a consequence of expansion of the universe. We study the effect driven by an expanding background that is asymptotically Minkowski in the past and future. The differential equation that governs the time mode function is obtained for the conformal coupling case and, although its solution is nonanalytic, within an approximation that preserves the characteristics of the terms that break analyticity, analytic solutions are obtained. Thus, by means of Bogolyubov transformations technique, the number density of particles created is obtained, which can be compared to exact solutions already present in literature for scalar and Dirac particles. The spectrum of the created particles was obtained and it was found that it is a generalization of the scalar field case, which converges to the scalar field one when the specific terms concerning the Elko field are dropped out. We also found that lighter Elko particles are created in larger quantities than the Dirac fermionic particles. By considering the Elko particles as candidate to the dark matter in the universe, such result shows that there are more light dark matter (Elko) particles created by the gravitational effects in the universe than baryonic (fermionic) matter, in agreement to the standard model.

Hidden conformal symmetry in Randall–Sundrum 2 model: Universal fermion localization by torsion

In this manuscript we describe a hidden conformal symmetry of the second Randall–Sundrum model (RS2). We show how this can be used to localize fermions of both chiralities. The conformal symmetry leaves few free dimensionless constants and constrains the allowed interactions. In this formulation the warping of the extra dimension emerges from a partial breaking of the conformal symmetry in five dimensions. The solution of the system can be described in two alternative gauges: by the metric or by the conformon. By considering this as a fundamental symmetry we construct a conformally invariant action for a vector field which provides a massless photon localized over a Minkowski brane. This is obtained by a conformal non-minimal coupling that breaks the gauge symmetry in five dimensions. We further consider a generalization of the model by including conformally invariant torsion. By coupling torsion non-minimally to fermions we obtain a localized zero mode of both chiralities completing the consistence of the model. The inclusion of torsion introduces a fermion quartic interaction that can be used to probe the existence of large extra dimensions and the validity of the model. This seems to point to the fact that conformal symmetry may be more fundamental than gauge symmetry and that this is the missing ingredient for the full consistence of RS scenarios.

The Ca2+ influx through the mammalian skeletal muscle dihydropyridine receptor is irrelevant for muscle performance

Skeletal muscle excitation–contraction (EC) coupling is initiated by sarcolemmal depolarization, which is translated into a conformational change of the dihydropyridine receptor (DHPR), which in turn activates sarcoplasmic reticulum (SR) Ca2+ release to trigger muscle contraction. During EC coupling, the mammalian DHPR embraces functional duality, as voltage sensor and l-type Ca2+ channel. Although its unique role as voltage sensor for conformational EC coupling is firmly established, the conventional function as Ca2+ channel is still enigmatic. Here we show that Ca2+ influx via DHPR is not necessary for muscle performance by generating a knock-in mouse where DHPR-mediated Ca2+ influx is eliminated. Homozygous knock-in mice display SR Ca2+ release, locomotor activity, motor coordination, muscle strength and susceptibility to fatigue comparable to wild-type controls, without any compensatory regulation of multiple key proteins of the EC coupling machinery and Ca2+ homeostasis. These findings support the hypothesis that the DHPR-mediated Ca2+ influx in mammalian skeletal muscle is an evolutionary remnant.

Beyond the growth rate of cosmic structure: Testing modified gravity models with an extra degree of freedom

In ``modified'' gravity the observed acceleration of the universe is explained by changing the gravitational force law or the number of degrees of freedom in the gravitational sector. Both possibilities can be tested by measurements of cosmological structure formation. In this paper we elaborate the details of such tests using the Galileon model as a case study. We pay attention to the possibility that each new degree of freedom may have stochastically independent initial conditions, generating different types of potential well in the early universe and breaking complete correlation between density and velocity power spectra. This ``stochastic bias'' can confuse schemes to parametrize the predictions of modified gravity models, such as the use of the growth parameter $f$ alone. Using data from the WiggleZ Dark Energy Survey we show that it will be possible to obtain constraints using information about the cosmological-scale force law embedded in the multipole power spectra of redshift-space distortions. As an example, we obtain an upper limit on the strength of the conformal coupling to matter in the cubic Galileon model, giving $|1/M|\ensuremath{\lesssim}200/{M}_{\mathrm{P}}$. This allows the fifth-force to be stronger than gravity, but is consistent with zero coupling.