Nonlocal correlations transmitted between quantum dots via short topological superconductor.

We study the quasiparticle states and nonlocal correlations of a hybrid structure, comprising two quantum dots interconnected through a short-length topological superconducting nanowire hosting overlaping Majorana modes. We show that the hybridization between different components of this setup gives rise to the emergence of molecular states, which are responsible for nonlocal correlations. We inspect the resulting energy structure, focusing on the inter-dependence between the quasiparticles of individual quantum dots. We predict the existence of nonlocal effects, which could be accessed and probed by crossed Andreev reflection spectroscopy. Our study would be relevant to a recent experimental realization of the minimal Kitaev model [T. Dvir et al., Nature 614, 445 (2023) ], by considering its hybrid structure with side-attached quantum dots.

Subgap dynamics of double quantum dot coupled between superconducting and normal leads.

Dynamical processes induced by the external time-dependent fields can provide valuable insight into the characteristic energy scales of a given physical system. We investigate them here in a nanoscopic heterostructure, consisting of the double quantum dot coupled in series to the superconducting and the metallic reservoirs, analyzing its response to (i) abrupt bias voltage applied across the junction, (ii) sudden change of the energy levels, and imposed by (iii) their periodic driving. We explore subgap properties of this setup which are strictly related to the in-gap quasiparticles and discuss their signatures manifested in the time-dependent charge currents. The characteristic multi-mode oscillations, their beating patters and photon-assisted harmonics reveal a rich spectrum of dynamical features that might be important for designing the superconducting qubits.

Magnetic field effect on trivial and topological bound states of superconducting quantum dot.

We investigate the properties of a quantum dot embedded between the normal and superconducting leads which is additionally side-attached to the topological superconducting nanowire, hosting the Majorana modes. This setup enables formation of the trivial (finite-energy) bound states induced in the quantum dot through the superconducting proximity effect, coexisting/competing with the topological (zero-energy) mode transmitted from the topological superconductor. We analyze their interplay, focusing on a role played by the external magnetic field. To distinguish between these bound states we analyze the qualitative and quantitative features manifested in the subgap charge tunneling originating under nonequilibrium conditions from the Andreev (particle to hole) scattering processes.

Leakage of Majorana mode into correlated quantum dot nearby its singlet-doublet crossover.

We study quasiparticle spectrum of the correlated quantum dot (QD) deposited on superconducting (SC) substrate which is side-coupled to the Rashba nanochain, hosting Majorana end modes. Ground state of an isolated QD proximitized to SC reservoirs is represented either by the singly occupied site or BCS-type superposition of the empty and doubly occupied configurations. Quantum phase transition between these distinct ground states is spectroscopically manifested by the in-gap Andreev states which cross each other at the Fermi level. This qualitatively affects leakage of the Majorana mode from the side-attached nanowire. We inspect the spin-selective relationship between the trivial Andreev states and the leaking Majorana mode, considering (i) perfectly polarized case, when tunneling of one spin component is completely prohibited, and (ii) another one when both spins are hybridized with the nanowire but with different couplings.

Interplay between correlations and Majorana mode in proximitized quantum dot.

We study the low energy spectrum and transport properties of a correlated quantum dot coupled between normal and superconducting reservoirs and additionally hybridized with a topological superconducting nanowire, hosting the Majorana end-modes. In this setup the Majorana quasiparticle leaking into the quantum dot can be confronted simultaneously with the on-dot pairing and correlations. We study this interplay, focusing on the quantum phase transition from the spinless (BCS-type) to the spinful (singly occupied) configuration, where the subgap Kondo effect may arise. Using the selfconsistent perturbative treatment for correlations and the unbiased numerical renormalization group calculations we find that the Majorana mode has either constructive or destructive effect on the low-energy transport behavior of the quantum dot, depending on its spin. This spin-selective influence could be verified by means of the polarized STM spectroscopy.

Spin-sensitive interference due to Majorana state on the interface between normal and superconducting leads.

We investigate the subgap spectrum and transport properties of the quantum dot on the interface between the metallic and superconducting leads and additionally side-coupled to the edge of the topological superconducting (TS) chain, hosting the Majorana quasiparticle. Due to the chiral nature of the Majorana states only one spin component of the quantum dot electrons (say [Formula: see text]) is directly affected, however the proximity induced on-dot pairing transmits its influence on the opposite spin as well. We investigate the unique interferometric patterns driven by the Majorana quasiparticle that are different for each spin component. We also address the spin-sensitive interplay with the Kondo effect manifested at the same zero-energy and we come to the conclusion that quantum interferometry can unambiguously identify the Majorana quasiparticle.

Constructive influence of the induced electron pairing on the Kondo state.

Superconducting order and magnetic impurities are usually detrimental to each other. We show, however, that in nanoscopic objects the induced electron pairing can have constructive influence on the Kondo effect originating from the effective screening interactions. Such situation is possible at low temperatures in the quantum dots placed between the conducting and superconducting reservoirs, where the proximity induced electron pairing cooperates with the correlations amplifying the spin-exchange potential. The emerging Abrikosov-Suhl resonance, which is observable in the Andreev conductance, can be significantly enhanced by increasing the coupling to superconducting lead. We explain this intriguing tendency within the Anderson impurity model using: the generalized Schrieffer-Wolff canonical transformation, the second order perturbative treatment of the Coulomb repulsion, and the nonperturbative numerical renormalization group calculations. We also provide hints for experimental observability of this phenomenon.

Novel non-local effects in three-terminal hybrid devices with quantum dot.

We predict non-local effect in the three-terminal hybrid device consisting of the quantum dot (QD) tunnel coupled to two normal and one superconducting reservoirs. It manifests itself as the negative non-local resistance and results from the competition between the ballistic electron transfer (ET) and the crossed Andreev scattering (CAR). The effect is robust both in the linear and non-linear regimes. In the latter case the screening of charges and the long-range interactions play significant role. We show that sign change of the non-local conductance depends on the subgap Shiba/Andreev states, and it takes place even in absence of the Coulomb interactions. The effect is large and can be experimentally verified using the four probe setup. Since the induced non-local voltage changes sign and magnitude upon varying the gate potential and/or coupling of the quantum dot to the superconducting lead, such measurement could hence provide a controlled and precise method to determine the positions of the Shiba/Andreev states. Our predictions ought to be contrasted with non-local effects observed hitherto in the three-terminal planar junctions where the residual negative non-local conductance has been observed at large voltages, related to the Thouless energy of quasiparticles tunneling through the superconducting slab.

Enhancements of the Andreev conductance due to emission/absorption of bosonic quanta.

We predict that the subgap spectrum and transport properties of the quantum dot embedded between superconducting and metallic reservoirs can be substantially enhanced by emission/absorption of external bosonic quanta. Upon tuning the gate voltage the in-gap Andreev states eventually interfere with each other. We explore the measurable signatures of such interference appearing in the differential conductance for both linear and nonlinear regimes.

In-gap states of a quantum dot coupled between a normal and a superconducting lead.

We study the in-gap states of a quantum dot hybridized with one conducting and another superconducting electrode. The proximity effect suppresses the electronic states in the entire subgap regime |ω| < Δ, where Δ denotes the energy gap of the superconductor. The Andreev scattering mechanism can induce, however, some in-gap states whose line-broadening (inverse life-time) is controlled by the hybridization of the quantum dot with the normal electrode. We show that the number of such Andreev bound states is substantially dependent on the competition between the Coulomb repulsion and the induced on-dot pairing. We discuss the signatures of these in-gap states in the tunneling conductance, especially in a low-bias regime.

Real space inhomogeneities in high temperature superconductors: the perspective of the two-component model.

The two-component model of high temperature superconductors in its real space version has been solved using Bogoliubov-de Gennes equations. The disorder in the electron and boson subsystem has been taken into account. It strongly modifies the superconducting properties and leads to local variations of the gap parameter and density of states. The assumption that the impurities mainly modify boson energies offers a natural explanation of the puzzling positive correlation between the positions of impurities and the values of the order parameter found in the scanning tunneling microscopy experiments.

A simple bubbling system for measuring radon (222Rn) gas concentrations in water samples based on the high solubility of radon in olive oil.

Based on the different levels of solubility of radon gas in organic solvents and water, a bubbling system has been developed to transfer radon gas, dissolving naturally in water samples, to an organic solvent, i.e. olive oil, which is known to be a good solvent of radon gas. The system features the application of a fixed volume of bubbling air by introducing a fixed volume of water into a flask mounted above the system, to displace an identical volume of air from an air cylinder. Thus a gravitational flow of water is provided without the need for pumping. Then, the flushing air (radon-enriched air) is directed through a vial containing olive oil, to achieve deposition of the radon gas by another bubbling process. Following this, the vial (containing olive oil) is measured by direct use of gamma ray spectrometry, without the need of any chemical or physical processing of the samples. Using a standard solution of 226Ra/222Rn, a lowest measurable concentration (LMC) of radon in water samples of 9.4 Bq L(-1) has been achieved (below the maximum contaminant level of 11 Bq L(-1)).

Bogoliubov shadow bands in the normal state of superconducting systems with strong pair fluctuations.

On the basis of a scenario where electron pairing is induced by resonant two-particle scattering (the boson-fermion model), we show how precursors of the superconducting state-in the form of overdamped Bogoliubov modes-emerge in the normal state upon approaching the transition temperature from above. This result is obtained by a renormalization technique based on continuous unitary transformations (the flow equations), projecting out the coherent contributions in the electron spectral function from an incoherent background.

The role of cytochrome 2B1 substrate recognition site residues 115, 294, 297, 298, and 362 in the oxidation of steroids and 7-alkoxycoumarins.

At least two substitutions were made at each of five amino acid residues in rat cytochrome P450 2B1 that align to residues of known importance in other P450s. The mutants were histidine tagged for purification from Escherichia coli, and the proteins were assessed for testosterone and 7-alkoxycoumarin oxidation. Alteration of each of the sites studied, Phe-115, Ser-294, Phe-297, Ala-298, and Leu-362, was found to affect overall enzyme activity or the metabolite profile. In particular, most of the mutants, excluding F297A, A298G, and L362F, exhibited significantly altered ratios of 16alpha-hydroxytestosterone:16beta-hydroxytestosterone, with the most dramatic alteration being displayed by A298V. Four 7-butoxycoumarin metabolites were produced by CYP2B1, of which two, 7-hydroxycoumarin and 7-(3-hydroxybutoxy)coumarin, were formed at nearly equal rates. Several mutants, F115A, F297A, F297I, and A298V, exhibited an increased predominance of one of the metabolites. The results from this study illustrate the conservation of functionally important residues across P450 subfamilies and families.

Phenylalanine and tryptophan scanning mutagenesis of CYP3A4 substrate recognition site residues and effect on substrate oxidation and cooperativity.

Phenylalanine and/or tryptophan scanning mutagenesis was performed at 15 sites within CYP3A4 proposed to be involved in substrate specificity or cooperativity. The sites were chosen on the basis of previous studies or from a comparison with the structure of P450(eryF) containing two molecules of androstenedione. The function of the 25 mutants was assessed in a reconstituted system using progesterone, testosterone, 7-benzyloxy-4-(trifluoromethyl)coumarin (7-BFC), and alpha-naphthoflavone (ANF) as substrates. CYP3A4 wild type displayed sigmoidal kinetics of ANF 5,6-oxide formation and 7-BFC debenzylation. Analysis of 12 mutants with significant steroid hydroxylase activity showed a lack of positive correlation between ANF oxidation and stimulation of progesterone 6beta-hydroxylation by ANF, indicating that ANF binds at two sites within CYP3A4. 7-BFC debenzylation was stimulated by progesterone and ANF, and 7-BFC did not inhibit testosterone or progesterone 6beta-hydroxylation. Correlational analysis showed no relationship between 7-BFC debenzylation and either progesterone or testosterone 6beta-hydroxylation. These data are difficult to explain with a two-site model of CYP3A4 but suggest that three subpockets exist within the active site. Interestingly, classification of the mutants according to their ability to oxidize the four substrates utilized in this study suggested that substrates do bind at preferred locations in the CYP3A4 binding pocket.

Identification and functional characterization of eight CYP3A4 protein variants.

The genetic component of the inter-individual variability in CYP3A4 activity has been estimated to be between 60% and 90%, but the underlying genetic factors remain largely unknown. A study of 213 Middle and Western European DNA samples resulted in the identification of 18 new CYP3A4 variants, including eight protein variants. A total of 7.5% of the population studied was found to be heterozygous for one of these variants. In a bacterial heterologous expression system, two mutants, R130Q and P416L, did not result in detectable P450 holoprotein. One mutant, T363M, expressed at significantly lower levels than wild-type CYP3A4. G56D, V170I, D174H and M445T were not significantly different when compared with wild-type CYP3A4 in expression or steroid hydroxylase activity. L373F displayed a significantly altered testosterone metabolite profile and a four-fold increase in the Km value for 1'-OH midazolam formation. The results suggest a limited contribution of CYP3A4 protein variants to the inter-individual variability of CYP3A4 activity in Caucasians. Some variants may, however, play a role in the atypical response to drugs or altered sensitivity to carcinogens.

Analysis of mammalian cytochrome P450 structure and function by site-directed mutagenesis.

Over the past decade, site-directed mutagenesis has become an essential tool in the study of mammalian cytochrome P450 structure-function relationships. Residues affecting substrate specificity, cooperativity, membrane localization, and interactions with redox partners have been identified using a combination of amino-acid sequence alignments, homology modeling, chimeragenesis, and site-directed mutagenesis. As homology modeling and substrate docking technology continue to improve, the ability to predict more precise functions for specific residues will also advance, making it possible to utilize site-directed mutagenesis to test these predictions. Future studies will employ site-directed mutagenesis to learn more about cytochrome P450 substrate access channels, to define the role of residues that do not lie within substrate recognition sites, to engineer additional soluble forms of microsomal cytochromes P450 for x-ray crystallography, and to engineer more efficient enzymes for drug activation and/or bioremediation.

Influence of P450 3A4 SRS-2 residues on cooperativity and/or regioselectivity of aflatoxin B(1) oxidation.

The major human liver drug-metabolizing cytochrome P450 enzymes P450 3A4 and P450 3A5 share >85% amino acid sequence identity yet exhibit different regioselectivity toward aflatoxin B(1) (AFB(1)) biotransformation [Gillam et al. (1995) Arch. Biochem. Biophys. 317, 74-384]. P450 3A4 prefers AFB1 3alpha-hydroxylation, which detoxifies and subsequently eliminates the hepatotoxin, over AFB1 exo-8,9-oxidation. P450 3A5, on the other hand, is a relatively sluggish 3alpha-hydroxylase and converts AFB(1) predominantly to the genotoxic exo-8,9-epoxide. Using a combination of approaches (sequence alignment, homology modeling and site-directed mutagenesis), we have previously identified several divergent residues in four of the six putative substrate recognition sites (SRSs) of P450 3A4, which when replaced individually with the corresponding amino acid of P450 3A5, resulted in a significant switch of the characteristic P450 3A4 AFB(1) regioselectivity toward that of P450 3A5 [Wang et al. (1998) Biochemistry 37, 12536-12545]. In particular, residues N206 and L210 in SRS-2 were found to be critical for AFB(1) detoxification via 3alpha-hydroxylation, and the corresponding mutants N206S and L210F most closely mimicked P450 3A5, not only in its regioselectivity of AFB(1) metabolism but also in its overall functional capacity. We have now further explored the plausible reasons for such relative inactivity of the SRS-2 mutants by examining N206S and additional mutants (L210A, L211F, L211A, and N206E) and found that the dramatically lowered activities of the N206S mutant are accompanied by a loss of cooperativity of AFB(1) oxidation. Molecular dynamics analyses with an existing P450 3A4 homology model [Szklarz and Halpert (1997) J. Comput. Aided Mol. Des. 11, 265] suggested that N206 (helix F) interacts with E244 (helix G), creating a salt bridge that stabilizes the protein structure and/or defines the active site cavity. To examine this possibility, several E244 mutants (E244A, V, N, S) were tested, of which E244S was the most notable for its relatively greater impairment of P450 3A4-dependent AFB(1) 3alpha-hydroxylation. However, the results with these E244 mutants failed to validate the N206-E244 interaction predicted from these molecular dynamics analyses. Collectively, our findings to date have led us to reconsider our original interpretations and to reexamine them in the light of AFB(1) molecular modeling analyses with a newly refined P450 3A4 homology model. These analyses predicted that F304 in SRS-4 (I-helix) plays a pivotal role in AFB(1) binding at the active site in either orientation leading to 3alpha- or exo-8,9-oxidation. Consistent with this prediction, conversion of F304 to Ala abolished P450 3A4-dependent AFB(1) 3alpha-hydroxylation and exo-8,9-oxidation.

cDNA cloning and initial characterization of CYP3A43, a novel human cytochrome P450.

The RACE amplification technology was used on a novel CYP3A-like exon 1 sequence detected during the reverse transcriptase/polymerase chain reaction analysis of human CYP3A gene expression. This resulted in the identification of cDNAs encompassing the complete coding sequence of a new member of the CYP3A gene subfamily, CYP3A43. Interestingly, the majority of the cDNAs identified were characterized by alternative splicing events such as exon skipping and complete or partial intron inclusion. CYP3A43 expression was detected in liver, kidney, pancreas, and prostate. The amino acid sequence is 75% identical to that of CYP3A4 and CYP3A5 and 71% identical to CYP3A7. CYP3A43 differs from CYP3A4 at six amino acid residues, found within the putative substrate recognition sites of CYP3A4, that are known to be determinants of substrate selectivity. The N terminus of CYP3A43 was modified for efficient expression of the protein in Escherichia coli, and a 6X histidine tag was added at the C terminus to facilitate purification. CYP3A43 gave a reduced carbon monoxide difference spectra with an absorbance maximum at 450 nm. The level of heterologous expression was significantly lower than that observed for CYP3A4 and CYP3A5. Immunoblot analyses revealed that CYP3A43 comigrates with CYP3A4 in polyacrylamide gel electrophoresis but does separate from CYP3A5. Monooxygenase assays were performed under a variety of conditions, several of which yielded reproducible, albeit low, testosterone hydroxylase activity. The findings from this study demonstrate that there is a novel CYP3A member expressed in human tissues, although its relative contribution to drug metabolism has yet to be ascertained.

Dual role of human cytochrome P450 3A4 residue Phe-304 in substrate specificity and cooperativity.

The structural basis of cooperativity of progesterone hydroxylation catalyzed by human cytochrome P450 3A4 has been investigated. A recent study suggested that substitution of larger side chains at positions Leu-211 and Asp-214 partially mimics the action of effector by reducing the size of the active site. Based on predictions from molecular modeling that Phe-304 in the highly conserved I helix is involved in both effector and substrate binding, a tryptophan residue was substituted at this position. The purified F304W mutant displayed hyperbolic progesterone hydroxylase kinetics, indicating a lack of homotropic cooperativity. However, the mutant remained responsive to stimulation by alpha-naphthoflavone, exhibiting a 2-fold decrease in the K(m) value for progesterone 6beta-hydroxylation in the presence of 25 microM effector. Combining substitutions to yield the triple mutant L211F/D214E/F304W maintained the V(max) and decreased the K(m) for progesterone 6beta-hydroxylation, minimized stimulation by alpha-naphthoflavone, and decreased the rate of alpha-naphthoflavone oxidation to one-eighth of the wild type. Interestingly, the DeltaA(max) for spectral binding of alpha-naphthoflavone was unaltered in L211F/D214E/F304W. Overall, the results suggest that progesterone and alpha-naphthoflavone are oxidized at separate locations within the P450 3A4 binding pocket, although both substrates appear to have equal access to the reactive oxygen.