Conformational Coupling Research Articles

Frictionless vs. Frictional Contact in Numerical Wear Predictions of Conformal and Non-conformal Sliding Couplings

The role of friction on wear evolution is manifold since it interplays with lubrication regime, nominal contact point, and contact pressure distribution. Nevertheless, in the literature many wear models simulate wear assuming frictionless contact conditions to simplify the analyses. That assumption, physically not realistic, often appears as a contradiction, permitted in numerical simulations where friction and wear can be considered independent phenomena.This study aims to validate the frictionless assumption in wear models with steady nominal contact point, such as in many common configurations, e.g. pin on plate/pin on disc. Wear was simulated according to the Archard wear law for both non-conformal and conformal pin-on-plate contact pairs in reciprocating motion, assuming frictionless and frictional contact conditions, varying the coefficient of friction f in the range 0–0.4. Finite Element wear models were developed in Ansys® both with implicit and explicit kinematics. Results demonstrate that the effect of friction on contact pressure distribution and worn profiles and on their evolution is negligible (differences lower than 0.05%). Thus, wear can be predicted using models in frictionless conditions which allow to extremely reduce the computational costs that represent a limit of FE wear simulations. Additionally, a procedure with implicit kinematics was compared to the explicit one resulting valid and computationally convenient, especially in case of non-conformal contact.

Plane-wave and wave-packet neutrino flavor oscillations in vacuum in conformal coupling models

We investigate neutrino flavor oscillations in vacuum within a general conformal coupling model. We first examine the flavor oscillations within the plane-wave description of neutrinos, and then we extend our analysis to the wave-packet-based formalism. In both cases, we derive the general formulas for the flavor transition probability in arbitrary static and spherically symmetric spacetimes. We thoroughly discuss and assess in both cases the different possible ways---dictated by the presence of the conformal coupling---of computing the flavor transition probability. We show that the conformal invariance of the Dirac equation implies that the effect of conformal coupling on neutrino flavor oscillations modifies the oscillation length but preserves the coherence length and unitarity. A detailed application to two-flavor neutrinos is then made, and a numerical analysis is conducted within the well-known chameleon conformal coupling model.

Screening models and neutrino oscillations

In screening models with scalar-matter conformal coupling, we study the flavor transition of neutrinos. We employ an analytical method for studying the oscillation phase in a spherically symmetric spacetime filled by a scalar field. Since the ambient matter density determines the scalar field’s behavior, an indirect environmental effect contributes to the flavor conversion inside matter. We evaluate the survival probabilities and show that the existence of the scalar field affects the oscillations of neutrinos. We discuss the results in the framework of screening mechanisms and the end, confront our results with observational data.

Heterotropic roles of divalent cations in the establishment of allostery and affinity maturation of integrin αXβ2.

SUMMARYAllosteric activation and silencing of leukocyte β2-integrins transpire through cation-dependent structural changes, which mediate integrin biosynthesis and recycling, and are essential to designing leukocyte-specific drugs. Stepwise addition of Mg2+ reveals two mutually coupled events for the αXβ2 ligand-binding domain—the αX I-domain—corresponding to allostery establishment and affinity maturation. Electrostatic alterations in the Mg2+-binding site establish long-range couplings, leading to both pH− and Mg2+-occupancy-dependent biphasic stability change in the αX I-domain fold. The ligand-binding sensorgrams show composite affinity events for the αX I-domain accounting for the multiplicity of the αX I-domain conformational states existing in the solution. On cell surfaces, increasing Mg2+ concentration enhanced adhesiveness of αXβ2. This work highlights how intrinsically flexible pH− and cation-sensitive architecture endows a unique dynamic continuum to the αI-domain structure on the intact integrin, thereby revealing the importance of allostery establishment and affinity maturation in both extracellular and intracellular integrin events.

Observational constraints on the massive neutrinos induced late-time cosmic acceleration

We investigate a late-time cosmological scenario at the both cosmological background and linear perturbative level which is based on a mass-less λ ϕ 4 theory in which the scalar field is inextricably coupled to massive neutrino matter with Z 2 symmetry by a well defined conformal coupling. The chosen coupling generically leads to the spontaneous symmetry breaking at late times, as the coupling builds up dynamically, such that the field acquires a non-zero mass proportional to the neutrino mass and rolls down slowly around the true ground state which emerges after spontaneous symmetry breaking. From our parametric estimations, we find the given scenario is well supported by the background level cosmological observations and is also in a good agreement with the evolution of growth of matter perturbations.

Ligand-induced transmembrane conformational coupling in monomeric EGFR

Single pass cell surface receptors regulate cellular processes by transmitting ligand-encoded signals across the plasma membrane via changes to their extracellular and intracellular conformations. This transmembrane signaling is generally initiated by ligand binding to the receptors in their monomeric form. While subsequent receptor-receptor interactions are established as key aspects of transmembrane signaling, the contribution of monomeric receptors has been challenging to isolate due to the complexity and ligand-dependence of these interactions. By combining membrane nanodiscs produced with cell-free expression, single-molecule Förster Resonance Energy Transfer measurements, and molecular dynamics simulations, we report that ligand binding induces intracellular conformational changes within monomeric, full-length epidermal growth factor receptor (EGFR). Our observations establish the existence of extracellular/intracellular conformational coupling within a single receptor molecule. We implicate a series of electrostatic interactions in the conformational coupling and find the coupling is inhibited by targeted therapeutics and mutations that also inhibit phosphorylation in cells. Collectively, these results introduce a facile mechanism to link the extracellular and intracellular regions through the single transmembrane helix of monomeric EGFR, and raise the possibility that intramolecular transmembrane conformational changes upon ligand binding are common to single-pass membrane proteins.

Conformational fingerprinting of allosteric modulators in metabotropic glutamate receptor 2.

Activation of G protein-coupled receptors (GPCRs) is an allosteric process. It involves conformational coupling between the orthosteric ligand binding site and the G protein binding site. Factors that bind at non-cognate ligand binding sites to alter the allosteric activation process are classified as allosteric modulators and represent a promising class of therapeutics with distinct modes of binding and action. For many receptors, how modulation of signaling is represented at the structural level is unclear. Here, we developed fluorescence resonance energy transfer (FRET) sensors to quantify receptor modulation at each of the three structural domains of metabotropic glutamate receptor 2 (mGluR2). We identified the conformational fingerprint for several allosteric modulators in live cells. This approach enabled us to derive a receptor-centric representation of allosteric modulation and to correlate structural modulation to the standard signaling modulation metrics. Single-molecule FRET analysis revealed that a NAM (egative allosteric modulator) increases the occupancy of one of the intermediate states while a positive allosteric modulator increases the occupancy of the active state. Moreover, we found that the effect of allosteric modulators on the receptor dynamics is complex and depend on the orthosteric ligand. Collectively, our findings provide a structural mechanism of allosteric modulation in mGluR2 and suggest possible strategies for design of future modulators.

Graphs of Hydrogen-Bond Networks to Dissect Protein Conformational Dynamics.

Dynamic hydrogen bonds and hydrogen-bond networks are ubiquitous in proteins and protein complexes. Functional roles that have been assigned to hydrogen-bond networks include structural plasticity for protein function, allosteric conformational coupling, long-distance proton transfers, and transient storage of protons. Advances in structural biology provide invaluable insights into architectures of large proteins and protein complexes of direct interest to human physiology and disease, including G Protein Coupled Receptors (GPCRs) and the SARS-Covid-19 spike protein S, and give rise to the challenge of how to identify those interactions that are more likely to govern protein dynamics. This Perspective discusses applications of graph-based algorithms to dissect dynamical hydrogen-bond networks of protein complexes, with illustrations for GPCRs and spike protein S. H-bond graphs provide an overview of sites in GPCR structures where hydrogen-bond dynamics would be required to assemble longer-distance networks between functionally important motifs. In the case of spike protein S, graphs identify regions of the protein where hydrogen bonds rearrange during the reaction cycle and where local hydrogen-bond networks likely change in a virus variant of concern.

Special cosmological models derived from the semiclassical Einstein equation on flat FLRW space-times

This article presents numerical work on a special case of the cosmological semiclassical Einstein equation (SCE). The SCE describes the interaction of relativistic quantum matter by the expected value of the renormalized stress–energy tensor of a quantum field with classical gravity. Here, we consider a free, massless scalar field with general (not necessarily conformal) coupling to curvature. In a cosmological scenario with flat spatial sections for special choices of the initial conditions, we observe a separation of the dynamics of the quantum degrees of freedom from the dynamics of the scale factor, which extends a classical result by Starobinski (1980 Phys. Lett. B 91 99–102) to general coupling. For this new equation of fourth order governing the dynamics of the scale factor, we study numerical solutions. Typical solutions show a radiation-like Big Bang for the early Universe and de Sitter-like expansion for the late Universe. We discuss a specific solution to the cosmological horizon problem that can be produced by tuning parameters in the given equation. Although the model proposed here only contains massless matter, we give a preliminary comparison of the obtained cosmology with the ΛCDM standard model of cosmology and investigate parameter ranges in which the new models, to a certain extent, is capable of assimilating standard cosmology.

Ligand-induced transmembrane conformational coupling in monomeric EGFR

Ligand-induced transmembrane conformational coupling in monomeric EGFR

Ligand-induced transmembrane conformational coupling in monomeric EGFR

Ligand-induced transmembrane conformational coupling in monomeric EGFR

Ligand-induced transmembrane conformational coupling in monomeric EGFR

Ligand-induced transmembrane conformational coupling in monomeric EGFR

Reheating and dark matter freeze-in in the Higgs-R2 inflation model

We study the post-inflationary dynamics for reheating and freeze-in dark matter in the Higgs-R2 inflation model. Taking the perturbative approach for reheating, we determine the evolution of the temperature for radiation bath produced during reheating and determine the maximum and reheating temperatures of the Universe. Adopting a singlet scalar dark matter with a conformal non-minimal coupling and a vanishing Higgs-portal coupling, we discuss the freeze-in production of dark matter both from the non-thermal scattering during reheating and the thermal scattering after reheating. We find that thermal scattering is dominant for dark matter production in our model due to the high reheating temperature. The reheating temperature in our model is determined dominantly by the Higgs condensate to be up to about 1014 GeV and dark matter with masses up to about 109 GeV can be produced with a correct relic density.

Fast full N-body simulations of generic modified gravity: conformal coupling models

We present mg-glam, a code developed for the very fast production of full N-body cosmological simulations in modified gravity (MG) models. We describe the implementation, numerical tests and first results of a large suite of cosmological simulations for three classes of MG models with conformal coupling terms: the f(R) gravity, symmetron and coupled quintessence models. Derived from the parallel particle-mesh code glam, mg-glam incorporates an efficient multigrid relaxation technique to solve the characteristic nonlinear partial differential equations of these models. For f(R) gravity, we have included new variants to diversify the model behaviour, and we have tailored the relaxation algorithms to these to maintain high computational efficiency. In a companion paper, we describe versions of this code developed for derivative coupling MG models, including the Vainshtein- and K-mouflage-type models. mg-glam can model the prototypes for most MG models of interest, and is broad and versatile. The code is highly optimised, with a tremendous speedup of a factor of more than a hundred compared with earlier N-body codes, while still giving accurate predictions of the matter power spectrum and dark matter halo abundance. mg-glam is ideal for the generation of large numbers of MG simulations that can be used in the construction of mock galaxy catalogues and the production of accurate emulators for ongoing and future galaxy surveys.

Bifurcated symmetry breaking in scalar-tensor gravity

We present models that simultaneously predict the presence of dark energy and cold dark matter along with slow-roll inflation. The dark energy density is found to be of order $(\text{a few meV}{)}^{4}$, and the mass of dark matter constituent is $\ensuremath{\approx}1\text{ }\text{ }\mathrm{meV}$. These numbers are given in terms of the present value of Hubble constant ${H}_{0}$ and the Plank energy ${M}_{\mathrm{P}}\text{ }=\text{ }1/\sqrt{16\ensuremath{\pi}{G}_{N}}$: they are $({H}_{0}{M}_{\mathrm{P}}{)}^{2}$ for the dark energy density and $({H}_{0}{M}_{\mathrm{P}}{)}^{1/2}$ for the dark matter constituent mass. The basic theoretical framework we work in is a multiscalar tensor gravity with nontrivial conformal coupling to the Ricci scalar curvature in the Lagrangian density. The key for a right amount of dark energy is to incorporate in a novel way the spatially homogeneous kinetic contribution of Nambu-Goldstone modes in a spontaneously broken multiscalar field sector. Proposed theories are made consistent with general relativity tests at small cosmological distances, yet are different from general relativity at cosmological scales. Dark matter is generated as a spatially inhomogeneous component of the scalar system, with a roughly comparable amount to the dark energy. In some presented models a cosmological bifurcation of symmetry breaking of the scalar sector is triggered by the spontaneous breaking of electroweak $\mathrm{SU}(2)\ifmmode\times\else\texttimes\fi{}\mathrm{U}(1)$ gauge symmetry, hence the separation occurring simultaneously at the electroweak phase transition. The best experimental method to test presented models is to search for the fifth-force type of scalar exchange interaction with a force range, $O({10}^{\ensuremath{-}2})\text{ }\text{ }\mathrm{cm}$, whose coupling to matter is basically of gravitational strength.

Intersubunit Coupling Enables Fast CO2-Fixation by Reductive Carboxylases.

Enoyl-CoA carboxylases/reductases (ECRs) are some of the most efficient CO2-fixing enzymes described to date. However, the molecular mechanisms underlying the extraordinary catalytic activity of ECRs on the level of the protein assembly remain elusive. Here we used a combination of ambient-temperature X-ray free electron laser (XFEL) and cryogenic synchrotron experiments to study the structural organization of the ECR from Kitasatospora setae. The K. setae ECR is a homotetramer that differentiates into a pair of dimers of open- and closed-form subunits in the catalytically active state. Using molecular dynamics simulations and structure-based mutagenesis, we show that catalysis is synchronized in the K. setae ECR across the pair of dimers. This conformational coupling of catalytic domains is conferred by individual amino acids to achieve high CO2-fixation rates. Our results provide unprecedented insights into the dynamic organization and synchronized inter- and intrasubunit communications of this remarkably efficient CO2-fixing enzyme during catalysis.

Dynamics and physiological meaning of complexes between ion channels and integrin receptors: the case of Kv11.1.

The cellular functions are regulated by a complex interplay of diffuse and local signals. Studying the latter is challenging, but experimental work in cell physiology has led to recognize that understanding a cell's dynamics requires a deep comprehension of local fluctuations of cytosolic regulators. Macromolecular complexes are major determinants of local signaling. Multienzyme assemblies limit the diffusion restriction to reaction kinetics by direct exchange of metabolites. Likewise, close coupling of ion channels and transporters modulates the ion concentration around a channel mouth or transporter binding site. Extreme signal locality is brought about by conformational coupling between membrane proteins, as is typical of mechanotransduction. A paradigmatic case is integrin-mediated cell adhesion. Sensing the extracellular microenvironment and providing an appropriate response are essential in growth and development and have innumerable pathological implications. The process involves bidirectional signal transduction by complex supramolecular structures that link integrin receptors to ion channels and transporters, growth factor receptors, cytoskeletal elements, and other regulatory elements. The dynamics of such complexes are only beginning to be understood. A thoroughly studied example is the association between integrin receptors and the voltage-gated K+ channels Kv11.1. These channels are widely expressed in early embryos, where their physiological roles are poorly understood and apparently different from the shaping of action potential firing in the adult. Hints about these roles come from studies in cancer cells, where Kv11.1 is often overexpressed and appears to reassume functions it presumably exerts during embryogenesis, such as controlling cell proliferation/differentiation, apoptosis, and migration. Kv11.1 is implicated in these processes through its linking to integrin subunits, which in turn regulates channel expression. Specific cellular functions, such as proliferation and migration, appear to be modulated by distinct conformational states of the channel (e.g., open and closed), whose balance is affected by the link with integrin subunits.

Glutathione binding to the plant AtAtm3 transporter and implications for the conformational coupling of ABC transporters.

The ATP binding cassette (ABC) transporter of mitochondria (Atm) from Arabidopsis thaliana (AtAtm3) has been implicated in the maturation of cytosolic iron-sulfur proteins and heavy metal detoxification, plausibly by exporting glutathione derivatives. Using single-particle cryo-electron microscopy, we have determined four structures of AtAtm3 in three different conformational states: two inward-facing conformations (with and without bound oxidized glutathione [GSSG]), together with closed and outward-facing states stabilized by MgADP-VO4. These structures not only provide a structural framework for defining the alternating access transport cycle, but also reveal the paucity of cysteine residues in the glutathione binding site that could potentially form inhibitory mixed disulfides with GSSG. Despite extensive efforts, we were unable to prepare the ternary complex of AtAtm3 containing both GSSG and MgATP. A survey of structurally characterized type IV ABC transporters that includes AtAtm3 establishes that while nucleotides are found associated with all conformational states, they are effectively required to stabilize occluded, closed, and outward-facing conformations. In contrast, transport substrates have only been observed associated with inward-facing conformations. The absence of structures with dimerized nucleotide binding domains containing both nucleotide and transport substrate suggests that this form of the ternary complex exists only transiently during the transport cycle.

Fluorescence lifetime imaging microscopy reveals sodium pump dimers in live cells

The sodium-potassium ATPase (Na/K-ATPase, NKA) establishes ion gradients that facilitate many physiological functions including action potentials and secondary transport processes. NKA comprises a catalytic subunit (alpha) that interacts closely with an essential subunit (beta) and regulatory transmembrane micropeptides called FXYD proteins. In the heart, a key modulatory partner is the FXYD protein phospholemman (PLM, FXYD1), but the stoichiometry of the alpha–beta–PLM regulatory complex is unknown. Here, we used fluorescence lifetime imaging and spectroscopy to investigate the structure, stoichiometry, and affinity of the NKA-regulatory complex. We observed a concentration-dependent binding of the subunits of NKA–PLM regulatory complex, with avid association of the alpha subunit with the essential beta subunit as well as lower affinity alpha–alpha and alpha–PLM interactions. These data provide the first evidence that, in intact live cells, the regulatory complex is composed of two alpha subunits associated with two beta subunits, decorated with two PLM regulatory subunits. Docking and molecular dynamics (MD) simulations generated a structural model of the complex that is consistent with our experimental observations. We propose that alpha–alpha subunit interactions support conformational coupling of the catalytic subunits, which may enhance NKA turnover rate. These observations provide insight into the pathophysiology of heart failure, wherein low NKA expression may be insufficient to support formation of the complete regulatory complex with the stoichiometry (alpha-beta-PLM)2.

No Evidence of Kinetic Screening in Simulations of Merging Binary Neutron Stars beyond General Relativity.

We have conducted fully relativistic simulations in a class of scalar-tensor theories with derivative self-interactions and screening of local scales. By using high-resolution shock-capturing methods and a nonvanishing shift vector, we have managed to avoid issues plaguing similar attempts in the past. We have first confirmed recent results by ourselves in spherical symmetry, obtained with an approximate approach and pointing at a partial breakdown of the screening in black-hole collapse. Then, we considered the late inspiral and merger of binary neutron stars. We found that screening tends to suppress the (subdominant) dipole scalar emission, but not the (dominant) quadrupole scalar mode. Our results point at quadrupole scalar signals as large as (or even larger than) in Fierz-Jordan-Brans-Dicke theories with the same conformal coupling, for strong-coupling scales in the MeV range that we can simulate.