Spider toxin inhibits gating pore currents underlying periodic paralysis.

PubMed

Männikkö, Roope; Shenkarev, Zakhar O; Thor, Michael G; Berkut, Antonina A; Myshkin, Mikhail Yu; Paramonov, Alexander S; Kulbatskii, Dmitrii S; Kuzmin, Dmitry A; Sampedro Castañeda, Marisol; King, Louise; Wilson, Emma R; Lyukmanova, Ekaterina N; Kirpichnikov, Mikhail P; Schorge, Stephanie; Bosmans, Frank; Hanna, Michael G; Kullmann, Dimitri M; Vassilevski, Alexander A

2018-04-24

Gating pore currents through the voltage-sensing domains (VSDs) of the skeletal muscle voltage-gated sodium channel Na V 1.4 underlie hypokalemic periodic paralysis (HypoPP) type 2. Gating modifier toxins target ion channels by modifying the function of the VSDs. We tested the hypothesis that these toxins could function as blockers of the pathogenic gating pore currents. We report that a crab spider toxin Hm-3 from Heriaeus melloteei can inhibit gating pore currents due to mutations affecting the second arginine residue in the S4 helix of VSD-I that we have found in patients with HypoPP and describe here. NMR studies show that Hm-3 partitions into micelles through a hydrophobic cluster formed by aromatic residues and reveal complex formation with VSD-I through electrostatic and hydrophobic interactions with the S3b helix and the S3-S4 extracellular loop. Our data identify VSD-I as a specific binding site for neurotoxins on sodium channels. Gating modifier toxins may constitute useful hits for the treatment of HypoPP. Copyright © 2018 the Author(s). Published by PNAS.

Inter-subunit interactions across the upper voltage sensing-pore domain interface contribute to the concerted pore opening transition of Kv channels.

PubMed

Shem-Ad, Tzilhav; Irit, Orr; Yifrach, Ofer

2013-01-01

The tight electro-mechanical coupling between the voltage-sensing and pore domains of Kv channels lies at the heart of their fundamental roles in electrical signaling. Structural data have identified two voltage sensor pore inter-domain interaction surfaces, thus providing a framework to explain the molecular basis for the tight coupling of these domains. While the contribution of the intra-subunit lower domain interface to the electro-mechanical coupling that underlies channel opening is relatively well understood, the contribution of the inter-subunit upper interface to channel gating is not yet clear. Relying on energy perturbation and thermodynamic coupling analyses of tandem-dimeric Shaker Kv channels, we show that mutation of upper interface residues from both sides of the voltage sensor-pore domain interface stabilizes the closed channel state. These mutations, however, do not affect slow inactivation gating. We, moreover, find that upper interface residues form a network of state-dependent interactions that stabilize the open channel state. Finally, we note that the observed residue interaction network does not change during slow inactivation gating. The upper voltage sensing-pore interaction surface thus only undergoes conformational rearrangements during channel activation gating. We suggest that inter-subunit interactions across the upper domain interface mediate allosteric communication between channel subunits that contributes to the concerted nature of the late pore opening transition of Kv channels.

Thermodynamic coupling between activation and inactivation gating in potassium channels revealed by free energy molecular dynamics simulations.

PubMed

Pan, Albert C; Cuello, Luis G; Perozo, Eduardo; Roux, Benoît

2011-12-01

The amount of ionic current flowing through K(+) channels is determined by the interplay between two separate time-dependent processes: activation and inactivation gating. Activation is concerned with the stimulus-dependent opening of the main intracellular gate, whereas inactivation is a spontaneous conformational transition of the selectivity filter toward a nonconductive state occurring on a variety of timescales. A recent analysis of multiple x-ray structures of open and partially open KcsA channels revealed the mechanism by which movements of the inner activation gate, formed by the inner helices from the four subunits of the pore domain, bias the conformational changes at the selectivity filter toward a nonconductive inactivated state. This analysis highlighted the important role of Phe103, a residue located along the inner helix, near the hinge position associated with the opening of the intracellular gate. In the present study, we use free energy perturbation molecular dynamics simulations (FEP/MD) to quantitatively elucidate the thermodynamic basis for the coupling between the intracellular gate and the selectivity filter. The results of the FEP/MD calculations are in good agreement with experiments, and further analysis of the repulsive, van der Waals dispersive, and electrostatic free energy contributions reveals that the energetic basis underlying the absence of inactivation in the F103A mutation in KcsA is the absence of the unfavorable steric interaction occurring with the large Ile100 side chain in a neighboring subunit when the intracellular gate is open and the selectivity filter is in a conductive conformation. Macroscopic current analysis shows that the I100A mutant indeed relieves inactivation in KcsA, but to a lesser extent than the F103A mutant.

Crosstalk error correction through dynamical decoupling of single-qubit gates in capacitively coupled singlet-triplet semiconductor spin qubits

NASA Astrophysics Data System (ADS)

Buterakos, Donovan; Throckmorton, Robert E.; Das Sarma, S.

2018-01-01

In addition to magnetic field and electric charge noise adversely affecting spin-qubit operations, performing single-qubit gates on one of multiple coupled singlet-triplet qubits presents a new challenge: crosstalk, which is inevitable (and must be minimized) in any multiqubit quantum computing architecture. We develop a set of dynamically corrected pulse sequences that are designed to cancel the effects of both types of noise (i.e., field and charge) as well as crosstalk to leading order, and provide parameters for these corrected sequences for all 24 of the single-qubit Clifford gates. We then provide an estimate of the error as a function of the noise and capacitive coupling to compare the fidelity of our corrected gates to their uncorrected versions. Dynamical error correction protocols presented in this work are important for the next generation of singlet-triplet qubit devices where coupling among many qubits will become relevant.

Transcending binary logic by gating three coupled quantum dots.

PubMed

Klein, Michael; Rogge, S; Remacle, F; Levine, R D

2007-09-01

Physical considerations supported by numerical solution of the quantum dynamics including electron repulsion show that three weakly coupled quantum dots can robustly execute a complete set of logic gates for computing using three valued inputs and outputs. Input is coded as gating (up, unchanged, or down) of the terminal dots. A nanosecond time scale switching of the gate voltage requires careful numerical propagation of the dynamics. Readout is the charge (0, 1, or 2 electrons) on the central dot.

Voltage-Dependent Gating: Novel Insights from KCNQ1 Channels

PubMed Central

Cui, Jianmin

2016-01-01

Gating of voltage-dependent cation channels involves three general molecular processes: voltage sensor activation, sensor-pore coupling, and pore opening. KCNQ1 is a voltage-gated potassium (Kv) channel whose distinctive properties have provided novel insights on fundamental principles of voltage-dependent gating. 1) Similar to other Kv channels, KCNQ1 voltage sensor activation undergoes two resolvable steps; but, unique to KCNQ1, the pore opens at both the intermediate and activated state of voltage sensor activation. The voltage sensor-pore coupling differs in the intermediate-open and the activated-open states, resulting in changes of open pore properties during voltage sensor activation. 2) The voltage sensor-pore coupling and pore opening require the membrane lipid PIP2 and intracellular ATP, respectively, as cofactors, thus voltage-dependent gating is dependent on multiple stimuli, including the binding of intracellular signaling molecules. These mechanisms underlie the extraordinary KCNE1 subunit modification of the KCNQ1 channel and have significant physiological implications. PMID:26745405

Voltage-sensing domain of voltage-gated proton channel Hv1 shares mechanism of block with pore domains.

PubMed

Hong, Liang; Pathak, Medha M; Kim, Iris H; Ta, Dennis; Tombola, Francesco

2013-01-23

Voltage-gated sodium, potassium, and calcium channels are made of a pore domain (PD) controlled by four voltage-sensing domains (VSDs). The PD contains the ion permeation pathway and the activation gate located on the intracellular side of the membrane. A large number of small molecules are known to inhibit the PD by acting as open channel blockers. The voltage-gated proton channel Hv1 is made of two VSDs and lacks the PD. The location of the activation gate in the VSD is unknown and open channel blockers for VSDs have not yet been identified. Here, we describe a class of small molecules which act as open channel blockers on the Hv1 VSD and find that a highly conserved phenylalanine in the charge transfer center of the VSD plays a key role in blocker binding. We then use one of the blockers to show that Hv1 contains two intracellular and allosterically coupled gates. Copyright © 2013 Elsevier Inc. All rights reserved.

Coupling optical and electrical gating for electronic readout of quantum dot dynamics

NASA Astrophysics Data System (ADS)

Vasudevan, Smitha; Walczak, Kamil; Ghosh, Avik W.

2010-08-01

We explore the coherent transfer of electronic signatures from a strongly correlated, optically gated nanoscale quantum dot to a weakly interacting, electrically backgated microscale channel. In this unique side-coupled “ T ” geometry for transport, we predict a mechanism for detecting Rabi oscillations induced in the dot through quantum, rather than electrostatic means. This detection shows up directly in the dc conductance-voltage spectrum as a field-tunable split in the Fano lineshape arising due to interference between the dipole coupled dot states and the channel continuum. The split is further modified by the Coulomb interactions within the dot that influence the detuning of the Rabi oscillations. Furthermore, time resolving the signal we see clear beats when the Rabi frequencies approach the intrinsic Bohr frequencies in the dot. Capturing these coupled dynamics requires attention to memory effects and quantum interference in the channel as well as many-body effects in the dot. We accomplish this coupling by combining a Fock-space master equation for the dot dynamics with the phase-coherent, non-Markovian time-dependent nonequilibrium Green’s function transport formalism in the channel through a properly evaluated self-energy and a Coulomb integral. The strength of the interactions can further be modulated using a backgate that controls the degree of hybridization and charge polarization at the transistor surface.

Neutralisation of a single voltage sensor affects gating determinants in all four pore-forming S6 segments of Ca(V)1.2: a cooperative gating model.

PubMed

Beyl, Stanislav; Depil, Katrin; Hohaus, Annette; Stary-Weinzinger, Anna; Linder, Tobias; Timin, Eugen; Hering, Steffen

2012-10-01

Voltage sensors trigger the closed-open transitions in the pore of voltage-gated ion channels. To probe the transmission of voltage sensor signalling to the channel pore of Ca(V)1.2, we investigated how elimination of positive charges in the S4 segments (charged residues were replaced by neutral glutamine) modulates gating perturbations induced by mutations in pore-lining S6 segments. Neutralisation of all positively charged residues in IIS4 produced a functional channel (IIS4(N)), while replacement of the charged residues in IS4, IIIS4 and IVS4 segments resulted in nonfunctional channels. The IIS4(N) channel displayed activation kinetics similar to wild type. Mutations in a highly conserved structure motif on S6 segments ("GAGA ring": G432W in IS6, A780T in IIS6, G1193T in IIIS6 and A1503G in IVS6) induce strong left-shifted activation curves and decelerated channel deactivation kinetics. When IIS4(N) was combined with these mutations, the activation curves were shifted back towards wild type and current kinetics were accelerated. In contrast, 12 other mutations adjacent to the GAGA ring in IS6-IVS6, which also affect activation gating, were not rescued by IIS4(N). Thus, the rescue of gating distortions in segments IS6-IVS6 by IIS4(N) is highly position-specific. Thermodynamic cycle analysis supports the hypothesis that IIS4 is energetically coupled with the distantly located GAGA residues. We speculate that conformational changes caused by neutralisation of IIS4 are not restricted to domain II (IIS6) but are transmitted to gating structures in domains I, III and IV via the GAGA ring.

Coupling of activation and inactivation gate in a K+-channel: potassium and ligand sensitivity

PubMed Central

Ader, Christian; Schneider, Robert; Hornig, Sönke; Velisetty, Phanindra; Vardanyan, Vitya; Giller, Karin; Ohmert, Iris; Becker, Stefan; Pongs, Olaf; Baldus, Marc

2009-01-01

Potassium (K+)-channel gating is choreographed by a complex interplay between external stimuli, K+ concentration and lipidic environment. We combined solid-state NMR and electrophysiological experiments on a chimeric KcsA–Kv1.3 channel to delineate K+, pH and blocker effects on channel structure and function in a membrane setting. Our data show that pH-induced activation is correlated with protonation of glutamate residues at or near the activation gate. Moreover, K+ and channel blockers distinctly affect the open probability of both the inactivation gate comprising the selectivity filter of the channel and the activation gate. The results indicate that the two gates are coupled and that effects of the permeant K+ ion on the inactivation gate modulate activation-gate opening. Our data suggest a mechanism for controlling coordinated and sequential opening and closing of activation and inactivation gates in the K+-channel pore. PMID:19661921

Dynamics of internal pore opening in KV channels probed by a fluorescent unnatural amino acid

PubMed Central

Kalstrup, Tanja; Blunck, Rikard

2013-01-01

Atomic-scale models on the gating mechanism of voltage-gated potassium channels (Kv) are based on linear interpolations between static structures of their initial and final state derived from crystallography and molecular dynamics simulations, and, thus, lack dynamic structural information. The lack of information on dynamics and intermediate states makes it difficult to associate the structural with the dynamic functional data obtained with electrophysiology. Although voltage-clamp fluorometry fills this gap, it is limited to sites extracellularly accessible, when the key region for gating is located at the cytosolic side of the channels. Here, we solved this problem by performing voltage-clamp fluorometry with a fluorescent unnatural amino acid. By using an orthogonal tRNA-synthetase pair, the fluorescent unnatural amino acid was incorporated in the Shaker voltage-gated potassium channel at key regions that were previously inaccessible. Thus, we defined which parts act independently and which parts act cooperatively and found pore opening to occur in two sequential transitions. PMID:23630265

Structure of a prokaryotic sodium channel pore reveals essential gating elements and an outer ion binding site common to eukaryotic channels

PubMed Central

Shaya, David; Findeisen, Felix; Abderemane-Ali, Fayal; Arrigoni, Cristina; Wong, Stephanie; Nurva, Shailika Reddy; Loussouarn, Gildas; Minor, Daniel L.

2013-01-01

Voltage-gated sodium channels (NaVs) are central elements of cellular excitation. Notwithstanding advances from recent bacterial NaV (BacNaV) structures, key questions about gating and ion selectivity remain. Here, we present a closed conformation of NaVAe1p, a pore-only BacNaV derived from NaVAe1, a BacNaV from the arsenite oxidizer Alkalilimnicola ehrlichei found in Mono Lake, California, that provides insight into both fundamental properties. The structure reveals a pore domain in which the pore-lining S6 helix connects to a helical cytoplasmic tail. Electrophysiological studies of full-length BacNaVs show that two elements defined by the NaVAe1p structure, an S6 activation gate position and the cytoplasmic tail ‘neck’, are central to BacNaV gating. The structure also reveals the selectivity filter ion entry site, termed the ‘outer ion’ site. Comparison with mammalian voltage-gated calcium channel (CaV) selectivity filters, together with functional studies shows that this site forms a previously unknown determinant of CaV high affinity calcium binding. Our findings underscore commonalities between BacNaVs and eukaryotic voltage-gated channels and provide a framework for understanding gating and ion permeation in this superfamily. PMID:24120938

Structure of a prokaryotic sodium channel pore reveals essential gating elements and an outer ion binding site common to eukaryotic channels.

PubMed

Shaya, David; Findeisen, Felix; Abderemane-Ali, Fayal; Arrigoni, Cristina; Wong, Stephanie; Nurva, Shailika Reddy; Loussouarn, Gildas; Minor, Daniel L

2014-01-23

Voltage-gated sodium channels (NaVs) are central elements of cellular excitation. Notwithstanding advances from recent bacterial NaV (BacNaV) structures, key questions about gating and ion selectivity remain. Here, we present a closed conformation of NaVAe1p, a pore-only BacNaV derived from NaVAe1, a BacNaV from the arsenite oxidizer Alkalilimnicola ehrlichei found in Mono Lake, California, that provides insight into both fundamental properties. The structure reveals a pore domain in which the pore-lining S6 helix connects to a helical cytoplasmic tail. Electrophysiological studies of full-length BacNaVs show that two elements defined by the NaVAe1p structure, an S6 activation gate position and the cytoplasmic tail "neck", are central to BacNaV gating. The structure also reveals the selectivity filter ion entry site, termed the "outer ion" site. Comparison with mammalian voltage-gated calcium channel (CaV) selectivity filters, together with functional studies, shows that this site forms a previously unknown determinant of CaV high-affinity calcium binding. Our findings underscore commonalities between BacNaVs and eukaryotic voltage-gated channels and provide a framework for understanding gating and ion permeation in this superfamily. © 2013. Published by Elsevier Ltd. All rights reserved.

Asynchronous Movements Prior to Pore Opening in NMDA Receptors

PubMed Central

Kazi, Rashek; Gan, Quan; Talukder, Iehab; Markowitz, Michael; Salussolia, Catherine L.

2013-01-01

Glutamate-gated ion channels embedded within the neuronal membrane are the primary mediators of fast excitatory synaptic transmission in the CNS. The ion channel of these glutamate receptors contains a pore-lining transmembrane M3 helix surrounded by peripheral M1 and M4 helices. In the NMDA receptor subtype, opening of the ion channel pore, mediated by displacement of the M3 helices away from the central pore axis, occurs in a highly concerted fashion, but the associated temporal movements of the peripheral helices are unknown. To address the gating dynamics of the peripheral helices, we constrained the relative movements of the linkers that connect these helices to the ligand-binding domain using engineered cross-links, either within (intra-GluN1 or GluN2A) or between subunits. Constraining the peripheral linkers in any manner dramatically curtailed channel opening, highlighting the requirement for rearrangements of these peripheral structural elements for efficient gating to occur. However, the magnitude of this gating effect depended on the specific subunit being constrained, with the most dramatic effects occurring when the constraint was between subunits. Based on kinetic and thermodynamic analysis, our results suggest an asynchrony in the displacement of the peripheral linkers during the conformational and energetic changes leading to pore opening. Initially there are large-scale rearrangements occurring between the four subunits. Subsequently, rearrangements occur within individual subunits, mainly GluN2A, leading up to or in concert with pore opening. Thus, the conformational changes induced by agonist binding in NMDA receptors converge asynchronously to permit pore opening. PMID:23864691

Direct Structural Identification of Gas Induced Gate-Opening Coupled with Commensurate Adsorption in a Microporous Metal-Organic Framework.

PubMed

Banerjee, Debasis; Wang, Hao; Plonka, Anna M; Emge, Thomas J; Parise, John B; Li, Jing

2016-08-08

Gate-opening is a unique and interesting phenomenon commonly observed in flexible porous frameworks, where the pore characteristics and/or crystal structures change in response to external stimuli such as adding or removing guest molecules. For gate-opening that is induced by gas adsorption, the pore-opening pressure often varies for different adsorbate molecules and, thus, can be applied to selectively separate a gas mixture. The detailed understanding of this phenomenon is of fundamental importance to the design of industrially applicable gas-selective sorbents, which remains under investigated due to the lack of direct structural evidence for such systems. We report a mechanistic study of gas-induced gate-opening process of a microporous metal-organic framework, [Mn(ina)2 ] (ina=isonicotinate) associated with commensurate adsorption, by a combination of several analytical techniques including single crystal X-ray diffraction, in situ powder X-ray diffraction coupled with differential scanning calorimetry (XRD-DSC), and gas adsorption-desorption methods. Our study reveals that the pronounced and reversible gate opening/closing phenomena observed in [Mn(ina)2 ] are coupled with a structural transition that involves rotation of the organic linker molecules as a result of interaction of the framework with adsorbed gas molecules including carbon dioxide and propane. The onset pressure to open the gate correlates with the extent of such interaction. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A new mechanism of voltage-dependent gating exposed by KV10.1 channels interrupted between voltage sensor and pore.

PubMed

Tomczak, Adam P; Fernández-Trillo, Jorge; Bharill, Shashank; Papp, Ferenc; Panyi, Gyorgy; Stühmer, Walter; Isacoff, Ehud Y; Pardo, Luis A

2017-05-01

Voltage-gated ion channels couple transmembrane potential changes to ion flow. Conformational changes in the voltage-sensing domain (VSD) of the channel are thought to be transmitted to the pore domain (PD) through an α-helical linker between them (S4-S5 linker). However, our recent work on channels disrupted in the S4-S5 linker has challenged this interpretation for the KCNH family. Furthermore, a recent single-particle cryo-electron microscopy structure of K V 10.1 revealed that the S4-S5 linker is a short loop in this KCNH family member, confirming the need for an alternative gating model. Here we use "split" channels made by expression of VSD and PD as separate fragments to investigate the mechanism of gating in K V 10.1. We find that disruption of the covalent connection within the S4 helix compromises the ability of channels to close at negative voltage, whereas disconnecting the S4-S5 linker from S5 slows down activation and deactivation kinetics. Surprisingly, voltage-clamp fluorometry and MTS accessibility assays show that the motion of the S4 voltage sensor is virtually unaffected when VSD and PD are not covalently bound. Finally, experiments using constitutively open PD mutants suggest that the presence of the VSD is structurally important for the conducting conformation of the pore. Collectively, our observations offer partial support to the gating model that assumes that an inward motion of the C-terminal S4 helix, rather than the S4-S5 linker, closes the channel gate, while also suggesting that control of the pore by the voltage sensor involves more than one mechanism. © 2017 Tomczak et al.

A new mechanism of voltage-dependent gating exposed by KV10.1 channels interrupted between voltage sensor and pore

PubMed Central

Fernández-Trillo, Jorge; Bharill, Shashank; Panyi, Gyorgy; Stühmer, Walter; Isacoff, Ehud Y.

2017-01-01

Voltage-gated ion channels couple transmembrane potential changes to ion flow. Conformational changes in the voltage-sensing domain (VSD) of the channel are thought to be transmitted to the pore domain (PD) through an α-helical linker between them (S4–S5 linker). However, our recent work on channels disrupted in the S4–S5 linker has challenged this interpretation for the KCNH family. Furthermore, a recent single-particle cryo-electron microscopy structure of KV10.1 revealed that the S4–S5 linker is a short loop in this KCNH family member, confirming the need for an alternative gating model. Here we use “split” channels made by expression of VSD and PD as separate fragments to investigate the mechanism of gating in KV10.1. We find that disruption of the covalent connection within the S4 helix compromises the ability of channels to close at negative voltage, whereas disconnecting the S4–S5 linker from S5 slows down activation and deactivation kinetics. Surprisingly, voltage-clamp fluorometry and MTS accessibility assays show that the motion of the S4 voltage sensor is virtually unaffected when VSD and PD are not covalently bound. Finally, experiments using constitutively open PD mutants suggest that the presence of the VSD is structurally important for the conducting conformation of the pore. Collectively, our observations offer partial support to the gating model that assumes that an inward motion of the C-terminal S4 helix, rather than the S4–S5 linker, closes the channel gate, while also suggesting that control of the pore by the voltage sensor involves more than one mechanism. PMID:28360219

Improving the gate fidelity of capacitively coupled spin qubits

NASA Astrophysics Data System (ADS)

Wang, Xin; Barnes, Edwin

2015-03-01

Precise execution of quantum gates acting on two or multiple qubits is essential to quantum computation. For semiconductor spin qubits coupled via capacitive interaction, the best fidelity for a two-qubit gate demonstrated so far is around 70%, insufficient for fault-tolerant quantum computation. In this talk we present control protocols that may substantially improve the robustness of two-qubit gates against both nuclear noise and charge noise. Our pulse sequences incorporate simultaneous dynamical decoupling protocols and are simple enough for immediate experimental realization. Together with existing control protocols for single-qubit gates, our results constitute an important step toward scalable quantum computation using spin qubits. This work is done in collaboration with Sankar Das Sarma and supported by LPS-NSA-CMTC and IARPA-MQCO.

Neutralization of a single arginine residue gates open a two-pore domain, alkali-activated K+ channel

PubMed Central

Niemeyer, María Isabel; González-Nilo, Fernando D.; Zúñiga, Leandro; González, Wendy; Cid, L. Pablo; Sepúlveda, Francisco V.

2007-01-01

Potassium channels share a common selectivity filter that determines the conduction characteristics of the pore. Diversity in K+ channels is given by how they are gated open. TASK-2, TALK-1, and TALK-2 are two-pore region (2P) KCNK K+ channels gated open by extracellular alkalinization. We have explored the mechanism for this alkalinization-dependent gating using molecular simulation and site-directed mutagenesis followed by functional assay. We show that the side chain of a single arginine residue (R224) near the pore senses pH in TASK-2 with an unusual pKa of 8.0, a shift likely due to its hydrophobic environment. R224 would block the channel through an electrostatic effect on the pore, a situation relieved by its deprotonation by alkalinization. A lysine residue in TALK-2 fulfills the same role but with a largely unchanged pKa, which correlates with an environment that stabilizes its positive charge. In addition to suggesting unified alkaline pH-gating mechanisms within the TALK subfamily of channels, our results illustrate in a physiological context the principle that hydrophobic environment can drastically modulate the pKa of charged amino acids within a protein. PMID:17197424

Pore dynamics in lipid membranes

NASA Astrophysics Data System (ADS)

Gozen, I.; Dommersnes, P.

2014-09-01

Transient circular pores can open in plasma membrane of cells due to mechanical stress, and failure to repair such pores lead to cell death. Similar pores in the form of defects also exist among smectic membranes, such as in myelin sheaths or mitochondrial membranes. The formation and growth of membrane defects are associated with diseases, for example multiple sclerosis. A deeper understanding of membrane pore dynamics can provide a more refined picture of membrane integrity-related disease development, and possibly also treatment options and strategies. Pore dynamics is also of great importance regarding healthcare applications such as drug delivery, gene or as recently been implied, cancer therapy. The dynamics of pores significantly differ in stacks which are confined in 2D compared to those in cells or vesicles. In this short review, we will summarize the dynamics of different types of pores that can be observed in biological membranes, which include circular transient, fusion and hemi-fusion pores. We will dedicate a section to floral and fractal pores which were discovered a few years ago and have highly peculiar characteristics. Finally, we will discuss the repair mechanisms of large area pores in conjunction with the current cell membrane repair hypotheses.

Closed-state inactivation involving an internal gate in Kv4.1 channels modulates pore blockade by intracellular quaternary ammonium ions

PubMed Central

Fineberg, Jeffrey D.; Szanto, Tibor G.; Panyi, Gyorgy; Covarrubias, Manuel

2016-01-01

Voltage-gated K+ (Kv) channel activation depends on interactions between voltage sensors and an intracellular activation gate that controls access to a central pore cavity. Here, we hypothesize that this gate is additionally responsible for closed-state inactivation (CSI) in Kv4.x channels. These Kv channels undergo CSI by a mechanism that is still poorly understood. To test the hypothesis, we deduced the state of the Kv4.1 channel intracellular gate by exploiting the trap-door paradigm of pore blockade by internally applied quaternary ammonium (QA) ions exhibiting slow blocking kinetics and high-affinity for a blocking site. We found that inactivation gating seemingly traps benzyl-tributylammonium (bTBuA) when it enters the central pore cavity in the open state. However, bTBuA fails to block inactivated Kv4.1 channels, suggesting gated access involving an internal gate. In contrast, bTBuA blockade of a Shaker Kv channel that undergoes open-state P/C-type inactivation exhibits fast onset and recovery inconsistent with bTBuA trapping. Furthermore, the inactivated Shaker Kv channel is readily blocked by bTBuA. We conclude that Kv4.1 closed-state inactivation modulates pore blockade by QA ions in a manner that depends on the state of the internal activation gate. PMID:27502553

Aromatic–aromatic interactions between residues in KCa3.1 pore helix and S5 transmembrane segment control the channel gating process

PubMed Central

Garneau, Line; Klein, Hélène; Lavoie, Marie-France; Brochiero, Emmanuelle; Parent, Lucie

2014-01-01

The Ca2+-activated potassium channel KCa3.1 is emerging as a therapeutic target for a large variety of health disorders. One distinguishing feature of KCa3.1 is that the channel open probability at saturating Ca2+ concentrations (Pomax) is low, typically 0.1–0.2 for KCa3.1 wild type. This observation argues for the binding of Ca2+ to the calmodulin (CaM)–KCa3.1 complex, promoting the formation of a preopen closed-state configuration leading to channel opening. We have previously shown that the KCa3.1 active gate is most likely located at the level of the selectivity filter. As Ca2+-dependent gating of KCa3.1 originates from the binding of Ca2+ to CaM in the C terminus, the hypothesis of a gate located at the level of the selectivity filter requires that the conformational change initiated in the C terminus be transmitted to the S5 and S6 transmembrane helices, with a resulting effect on the channel pore helix directly connected to the selectivity filter. A study was thus undertaken to determine to what extent the interactions between the channel pore helix with the S5 and S6 transmembrane segments contribute to KCa3.1 gating. Molecular dynamics simulations first revealed that the largest contact area between the pore helix and the S5 plus S6 transmembrane helices involves residue F248 at the C-terminal end of the pore helix. Unitary current recordings next confirmed that modulating aromatic–aromatic interactions between F248 and W216 of the S5 transmembrane helical segment and/or perturbing the interactions between F248 and residues in S6 surrounding the glycine hinge G274 cause important changes in Pomax. This work thus provides the first evidence for a key contribution of the pore helix in setting Pomax by stabilizing the channel closed configuration through aromatic–aromatic interactions involving F248 of the pore helix. We propose that the interface pore helix/S5 constitutes a promising site for designing KCa3.1 potentiators. PMID:24470490

Direct Pore Binding as a Mechanism for Isoflurane Inhibition of the Pentameric Ligand-gated Ion Channel ELIC.

PubMed

Chen, Qiang; Kinde, Monica N; Arjunan, Palaniappa; Wells, Marta M; Cohen, Aina E; Xu, Yan; Tang, Pei

2015-09-08

Pentameric ligand-gated ion channels (pLGICs) are targets of general anesthetics, but molecular mechanisms underlying anesthetic action remain debatable. We found that ELIC, a pLGIC from Erwinia chrysanthemi, can be functionally inhibited by isoflurane and other anesthetics. Structures of ELIC co-crystallized with isoflurane in the absence or presence of an agonist revealed double isoflurane occupancies inside the pore near T237(6') and A244(13'). A pore-radius contraction near the extracellular entrance was observed upon isoflurane binding. Electrophysiology measurements with a single-point mutation at position 6' or 13' support the notion that binding at these sites renders isoflurane inhibition. Molecular dynamics simulations suggested that isoflurane binding was more stable in the resting than in a desensitized pore conformation. This study presents compelling evidence for a direct pore-binding mechanism of isoflurane inhibition, which has a general implication for inhibitory action of general anesthetics on pLGICs.

Direct Pore Binding as a Mechanism for Isoflurane Inhibition of the Pentameric Ligand-gated Ion Channel ELIC

PubMed Central

Chen, Qiang; Kinde, Monica N.; Arjunan, Palaniappa; Wells, Marta M.; Cohen, Aina E.; Xu, Yan; Tang, Pei

2015-01-01

Pentameric ligand-gated ion channels (pLGICs) are targets of general anesthetics, but molecular mechanisms underlying anesthetic action remain debatable. We found that ELIC, a pLGIC from Erwinia chrysanthemi, can be functionally inhibited by isoflurane and other anesthetics. Structures of ELIC co-crystallized with isoflurane in the absence or presence of an agonist revealed double isoflurane occupancies inside the pore near T237(6′) and A244(13′). A pore-radius contraction near the extracellular entrance was observed upon isoflurane binding. Electrophysiology measurements with a single-point mutation at position 6′ or 13′ support the notion that binding at these sites renders isoflurane inhibition. Molecular dynamics simulations suggested that isoflurane binding was more stable in the resting than in a desensitized pore conformation. This study presents compelling evidence for a direct pore-binding mechanism of isoflurane inhibition, which has a general implication for inhibitory action of general anesthetics on pLGICs. PMID:26346220

Molecular basis of usher pore gating in Escherichia coli pilus biogenesis.

PubMed

Volkan, Ender; Kalas, Vasilios; Pinkner, Jerome S; Dodson, Karen W; Henderson, Nadine S; Pham, Thieng; Waksman, Gabriel; Delcour, Anne H; Thanassi, David G; Hultgren, Scott J

2013-12-17

Extracellular fibers called chaperone-usher pathway pili are critical virulence factors in a wide range of Gram-negative pathogenic bacteria that facilitate binding and invasion into host tissues and mediate biofilm formation. Chaperone-usher pathway ushers, which catalyze pilus assembly, contain five functional domains: a 24-stranded transmembrane β-barrel translocation domain (TD), a β-sandwich plug domain (PLUG), an N-terminal periplasmic domain, and two C-terminal periplasmic domains (CTD1 and 2). Pore gating occurs by a mechanism whereby the PLUG resides stably within the TD pore when the usher is inactive and then upon activation is translocated into the periplasmic space, where it functions in pilus assembly. Using antibiotic sensitivity and electrophysiology experiments, a single salt bridge was shown to function in maintaining the PLUG in the TD channel of the P pilus usher PapC, and a loop between the 12th and 13th beta strands of the TD (β12-13 loop) was found to facilitate pore opening. Mutation of the β12-13 loop resulted in a closed PapC pore, which was unable to efficiently mediate pilus assembly. Deletion of the PapH terminator/anchor resulted in increased OM permeability, suggesting a role for the proper anchoring of pili in retaining OM integrity. Further, we introduced cysteine residues in the PLUG and N-terminal periplasmic domains that resulted in a FimD usher with a greater propensity to exist in an open conformation, resulting in increased OM permeability but no loss in type 1 pilus assembly. These studies provide insights into the molecular basis of usher pore gating and its roles in pilus biogenesis and OM permeability.

A localized interaction surface for voltage-sensing domains on the pore domain of a K+ channel.

PubMed

Li-Smerin, Y; Hackos, D H; Swartz, K J

2000-02-01

Voltage-gated K+ channels contain a central pore domain and four surrounding voltage-sensing domains. How and where changes in the structure of the voltage-sensing domains couple to the pore domain so as to gate ion conduction is not understood. The crystal structure of KcsA, a bacterial K+ channel homologous to the pore domain of voltage-gated K+ channels, provides a starting point for addressing this question. Guided by this structure, we used tryptophan-scanning mutagenesis on the transmembrane shell of the pore domain in the Shaker voltage-gated K+ channel to localize potential protein-protein and protein-lipid interfaces. Some mutants cause only minor changes in gating and when mapped onto the KcsA structure cluster away from the interface between pore domain subunits. In contrast, mutants producing large changes in gating tend to cluster near this interface. These results imply that voltage-sensing domains interact with localized regions near the interface between adjacent pore domain subunits.

Probing pore constriction in a ligand-gated ion channel by trapping a metal ion in the pore upon agonist dissociation.

PubMed

Pittel, Ilya; Witt-Kehati, Dvora; Degani-Katzav, Nurit; Paas, Yoav

2010-08-20

Eukaryotic pentameric ligand-gated ion channels (pLGICs) are receptors activated by neurotransmitters to rapidly transport ions across cell membranes, down their electrochemical gradients. Recent crystal structures of two prokaryotic pLGICs were interpreted to imply that the extracellular side of the transmembrane pore constricts to close the channel (Hilf, R. J., and Dutzler, R. (2009) Nature 457, 115-118; Bocquet, N., Nury, H., Baaden, M., Le Poupon, C., Changeux, J. P., Delarue, M., and Corringer, P. J. (2009) Nature 457, 111-114). Here, we utilized a eukaryotic acetylcholine (ACh)-serotonin chimeric pLGIC that was engineered with histidines to coordinate a metal ion within the channel pore, at its cytoplasmic side. In a previous study, the access of Zn(2+) ions to the engineered histidines had been explored when the channel was either at rest (closed) or active (open) (Paas, Y., Gibor, G., Grailhe, R., Savatier-Duclert, N., Dufresne, V., Sunesen, M., de Carvalho, L. P., Changeux, J. P., and Attali, B. (2005) Proc. Natl. Acad. Sci. U.S.A. 102, 15877-15882). In this study, the interactions of Zn(2+) with the pore were probed upon agonist (ACh) dissociation that triggers the transition of the receptor from the active conformation to the resting conformation (i.e. during deactivation). Application of Zn(2+) onto ACh-bound open receptors obstructed their pore and prevented ionic flow. Removing ACh from its extracellular binding sites to trigger deactivation while Zn(2+) is still bound led to tight trapping of Zn(2+) within the pore. Together with single-channel recordings, made to explore single pore-blocking events, we show that dissociation of ACh causes the gate to shut on a Zn(2+) ion that effectively acts as a "foot in the door." We infer that, upon deactivation, the cytoplasmic side of the pore of the ACh-serotonin receptor chimera constricts to close the channel.

Gated access to the pore of a P2X receptor: structural implications for closed-open transitions.

PubMed

Kracun, Sebastian; Chaptal, Vincent; Abramson, Jeff; Khakh, Baljit S

2010-03-26

P2X receptors are ligand-gated cation channels that transition from closed to open states upon binding ATP. The crystal structure of the closed zebrafish P2X4.1 receptor directly reveals that the ion-conducting pathway is formed by three transmembrane domain 2 (TM2) alpha-helices, each being provided by the three subunits of the trimer. However, the transitions in TM2 that accompany channel opening are incompletely understood and remain unresolved. In this study, we quantified gated access to Cd(2+) at substituted cysteines in TM2 of P2X2 receptors in the open and closed states. Our data for the closed state are consistent with the zebrafish P2X4.1 structure, with isoleucines and threonines (Ile-332 and Thr-336) positioned one helical turn apart lining the channel wall on approach to the gate. Our data for the open state reveal gated access to deeper parts of the pore (Thr-339, Val-343, Asp-349, and Leu-353), suggesting the closed channel gate is between Thr-336 and Thr-339. We also found unexpected interactions between native Cys-348 and D349C that result in tight Cd(2+) binding deep within the intracellular vestibule in the open state. Interpreted with a P2X2 receptor structural model of the closed state, our data suggest that the channel gate opens near Thr-336/Thr-339 and is accompanied by movement of the pore-lining regions, which narrow toward the cytosolic end of TM2 in the open state. Such transitions would relieve the barrier to ion flow and render the intracellular vestibule less splayed during channel opening in the presence of ATP.

Voltage-Dependent Gating of hERG Potassium Channels

PubMed Central

Cheng, Yen May; Claydon, Tom W.

2012-01-01

The mechanisms by which voltage-gated channels sense changes in membrane voltage and energetically couple this with opening of the ion conducting pore has been the source of significant interest. In voltage-gated potassium (Kv) channels, much of our knowledge in this area comes from Shaker-type channels, for which voltage-dependent gating is quite rapid. In these channels, activation and deactivation are associated with rapid reconfiguration of the voltage-sensing domain unit that is electromechanically coupled, via the S4–S5 linker helix, to the rate-limiting opening of an intracellular pore gate. However, fast voltage-dependent gating kinetics are not typical of all Kv channels, such as Kv11.1 (human ether-à-go-go related gene, hERG), which activates and deactivates very slowly. Compared to Shaker channels, our understanding of the mechanisms underlying slow hERG gating is much poorer. Here, we present a comparative review of the structure–function relationships underlying activation and deactivation gating in Shaker and hERG channels, with a focus on the roles of the voltage-sensing domain and the S4–S5 linker that couples voltage sensor movements to the pore. Measurements of gating current kinetics and fluorimetric analysis of voltage sensor movement are consistent with models suggesting that the hERG activation pathway contains a voltage independent step, which limits voltage sensor transitions. Constraints upon hERG voltage sensor movement may result from loose packing of the S4 helices and additional intra-voltage sensor counter-charge interactions. More recent data suggest that key amino acid differences in the hERG voltage-sensing unit and S4–S5 linker, relative to fast activating Shaker-type Kv channels, may also contribute to the increased stability of the resting state of the voltage sensor. PMID:22586397

Micro-mechanical resonators for dynamically reconfigurable reduced voltage logic gates

NASA Astrophysics Data System (ADS)

Chappanda, K. N.; Ilyas, S.; Younis, M. I.

2018-05-01

Due to the limitations of transistor-based logic devices such as their poor performance at elevated temperature, alternative computing methods are being actively investigated. In this work, we present electromechanical logic gates using electrostatically coupled in-plane micro-cantilever resonators operated at modest vacuum conditions of 5 Torr. Operating in the first resonant mode, we demonstrate 2-bit XOR, 2- and 3-bit AND, 2- and 3-bit NOR, and 1-bit NOT gates; all condensed in the same device. Through the designed electrostatic coupling, the required voltage for the logic gates is reduced by 80%, along with the reduction in the number of electrical interconnects and devices per logic operation (contrary to transistors). The device is dynamically reconfigurable between any logic gates in real time without the need for any change in the electrical interconnects and the drive circuit. By operating in the first two resonant vibration modes, we demonstrate mechanical logic gates consisting of two 2-bit AND and two 2-bit XOR gates. The device is tested at elevated temperatures and is shown to be functional as a logic gate up to 150 °C. Also, the device has high reliability with demonstrated lifetime greater than 5  ×  1012 oscillations.

External Barium Affects the Gating of KCNQ1 Potassium Channels and Produces a Pore Block via Two Discrete Sites

PubMed Central

Gibor, Gilad; Yakubovich, Daniel; Peretz, Asher; Attali, Bernard

2004-01-01

The pore properties and the reciprocal interactions between permeant ions and the gating of KCNQ channels are poorly understood. Here we used external barium to investigate the permeation characteristics of homomeric KCNQ1 channels. We assessed the Ba2+ binding kinetics and the concentration and voltage dependence of Ba2+ steady-state block. Our results indicate that extracellular Ba2+ exerts a series of complex effects, including a voltage-dependent pore blockade as well as unique gating alterations. External barium interacts with the permeation pathway of KCNQ1 at two discrete and nonsequential sites. (a) A slow deep Ba2+ site that occludes the channel pore and could be simulated by a model of voltage-dependent block. (b) A fast superficial Ba2+ site that barely contributes to channel block and mostly affects channel gating by shifting rightward the voltage dependence of activation, slowing activation, speeding up deactivation kinetics, and inhibiting channel inactivation. A model of voltage-dependent block cannot predict the complex impact of Ba2+ on channel gating in low external K+ solutions. Ba2+ binding to this superficial site likely modifies the gating transitions states of KCNQ1. Both sites appear to reside in the permeation pathway as high external K+ attenuates Ba2+ inhibition of channel conductance and abolishes its impact on channel gating. Our data suggest that despite the high degree of homology of the pore region among the various K+ channels, KCNQ1 channels display significant structural and functional uniqueness. PMID:15226366

Exploration of the pore structure of a peptide-gated Na+channel

PubMed Central

Poët, Mallorie; Tauc, Michel; Lingueglia, Eric; Cance, Peggy; Poujeol, Philippe; Lazdunski, Michel; Counillon, Laurent

2001-01-01

The FMRF-amide-activated sodium channel (FaNaC), a member of the ENaC/Degenerin family, is a homotetramer, each subunit containing two transmembrane segments. We changed independently every residue of the first transmembrane segment (TM1) into a cysteine and tested each position’s accessibility to the cysteine covalent reagents MTSET and MTSES. Eleven mutants were accessible to the cationic MTSET, showing that TM1 faces the ion translocation pathway. This was confirmed by the accessibility of cysteines present in the acid-sensing ion channels and other mutations introduced in FaNaC TM1. Modification of accessibilities for positions 69, 71 and 72 in the open state shows that the gating mechanism consists of the opening of a constriction close to the intracellular side. The anionic MTSES did not penetrate into the channel, indicating the presence of a charge selectivity filter in the outer vestibule. Furthermore, amiloride inhibition resulted in the channel occlusion in the middle of the pore. Summarizing, the ionic pore of FaNaC includes a large aqueous cavity, with a charge selectivity filter in the outer vestibule and the gate close to the interior. PMID:11598003

Toward elucidating the heat activation mechanism of the TRPV1 channel gating by molecular dynamics simulation.

PubMed

Wen, Han; Qin, Feng; Zheng, Wenjun

2016-12-01

As a key cellular sensor, the TRPV1 cation channel undergoes a gating transition from a closed state to an open state in response to various physical and chemical stimuli including noxious heat. Despite years of study, the heat activation mechanism of TRPV1 gating remains enigmatic at the molecular level. Toward elucidating the structural and energetic basis of TRPV1 gating, we have performed molecular dynamics (MD) simulations (with cumulative simulation time of 3 μs), starting from the high-resolution closed and open structures of TRPV1 solved by cryo-electron microscopy. In the closed-state simulations at 30°C, we observed a stably closed channel constricted at the lower gate (near residue I679), while the upper gate (near residues G643 and M644) is dynamic and undergoes flickery opening/closing. In the open-state simulations at 60°C, we found higher conformational variation consistent with a large entropy increase required for the heat activation, and both the lower and upper gates are dynamic with transient opening/closing. Through ensemble-based structural analyses of the closed state versus the open state, we revealed pronounced closed-to-open conformational changes involving the membrane proximal domain (MPD) linker, the outer pore, and the TRP helix, which are accompanied by breaking/forming of a network of closed/open-state specific hydrogen bonds. By comparing the closed-state simulations at 30°C and 60°C, we observed heat-activated conformational changes in the MPD linker, the outer pore, and the TRP helix that resemble the closed-to-open conformational changes, along with partial formation of the open-state specific hydrogen bonds. Some of the residues involved in the above key hydrogen bonds were validated by previous mutational studies. Taken together, our MD simulations have offered rich structural and dynamic details beyond the static structures of TRPV1, and promising targets for future mutagenesis and functional studies of the TRPV1 channel

Toward elucidating the heat activation mechanism of the TRPV1 channel gating by molecular dynamics simulation

PubMed Central

Wen, Han; Qin, Feng; Zheng, Wenjun

2016-01-01

As a key cellular sensor, the TRPV1 cation channel undergoes a gating transition from a closed state to an open state in response to various physical and chemical stimuli including noxious heat. Despite years of study, the heat activation mechanism of TRPV1 gating remains enigmatic at the molecular level. Toward elucidating the structural and energetic basis of TRPV1 gating, we have performed molecular dynamics (MD) simulations (with cumulative simulation time of 3 μs), starting from the high-resolution closed and open structures of TRPV1 solved by cryo-electron microscopy. In the closed-state simulations at 30°C, we observed a stably closed channel constricted at the lower gate (near residue I679), while the upper gate (near residues G643 and M644) is dynamic and undergoes flickery opening/closing. In the open-state simulations at 60°C, we found higher conformational variation consistent with a large entropy increase required for the heat activation, and both the lower and upper gates are dynamic with transient opening/closing. Through ensemble-based structural analyses of the closed state vs. the open state, we revealed pronounced closed-to-open conformational changes involving the membrane proximal domain (MPD) linker, the outer pore, and the TRP helix, which are accompanied by breaking/forming of a network of closed/open-state specific hydrogen bonds. By comparing the closed-state simulations at 30°C and 60°C, we observed heat-activated conformational changes in the MPD linker, the outer pore, and the TRP helix that resemble the closed-to-open conformational changes, along with partial formation of the open-state specific hydrogen bonds. Some of the residues involved in the above key hydrogen bonds were validated by previous mutational studies. Taken together, our MD simulations have offered rich structural and dynamic details beyond the static structures of TRPV1, and promising targets for future mutagenesis and functional studies of the TRPV1 channel

Human Aquaporin 4 Gating Dynamics under Perpendicularly-Oriented Electric-Field Impulses: A Molecular Dynamics Study

PubMed Central

Marracino, Paolo; Liberti, Micaela; Trapani, Erika; Burnham, Christian J.; Avena, Massimiliano; Garate, José-Antonio; Apollonio, Francesca; English, Niall J.

2016-01-01

Human aquaporin 4 has been studied using molecular dynamics (MD) simulations in the absence and presence of pulses of external static electric fields. The pulses were 10 ns in duration and 0.012–0.065 V/Å in intensity acting along both directions perpendicular to the pores. Water permeability and the dipolar response of all residues of interest (including the selectivity filter) within the pores have been studied. Results showed decreased levels of water osmotic permeability within aquaporin channels during orthogonally-oriented field impulses, although care must be taken with regard to statistical certainty. This can be explained observing enhanced “dipolar flipping” of certain key residues, especially serine 211, histidine 201, arginine 216, histidine 95 and cysteine 178. These residues are placed at the extracellular end of the pore (serine 211, histidine 201, and arginine 216) and at the cytoplasm end (histidine 95 and cysteine 178), with the key role in gating mechanism, hence influencing water permeability. PMID:27428954

Poring over two-pore channel pore mutants

PubMed Central

Penny, Christopher J.; Patel, Sandip

2016-01-01

Two-pore channels are members of the voltage-gated ion channel superfamily. They localise to the endolysosomal system and are likely targets for the Ca2+ mobilising messenger NAADP. In this brief review, we relate mutagenesis of the TPC pore to a recently published homology model and discuss how pore mutants are informing us of TPC function. Molecular physiology of these ubiquitous proteins is thus emerging. PMID:27226934

Multiple pore conformations driven by asynchronous movements of voltage sensors in a eukaryotic sodium channel

PubMed Central

Goldschen-Ohm, Marcel P.; Capes, Deborah L.; Oelstrom, Kevin M.; Chanda, Baron

2013-01-01

Voltage-dependent Na+ channels are crucial for electrical signalling in excitable cells. Membrane depolarization initiates asynchronous movements in four non-identical voltage-sensing domains of the Na+ channel. It remains unclear to what extent this structural asymmetry influences pore gating as compared with outwardly rectifying K+ channels, where channel opening results from a final concerted transition of symmetric pore gates. Here we combine single channel recordings, cysteine accessibility and voltage clamp fluorimetry to probe the relationships between voltage sensors and pore conformations in an inactivation deficient Nav1.4 channel. We observe three distinct conductance levels such that DI-III voltage sensor activation is kinetically correlated with formation of a fully open pore, whereas DIV voltage sensor movement underlies formation of a distinct subconducting pore conformation preceding inactivation in wild-type channels. Our experiments reveal that pore gating in sodium channels involves multiple transitions driven by asynchronous movements of voltage sensors. These findings shed new light on the mechanism of coupling between activation and fast inactivation in voltage-gated sodium channels. PMID:23322038

Reversal of Ion Charge Selectivity Renders the Pentameric Ligand-Gated Ion Channel GLIC Insensitive to Anesthetics

PubMed Central

Tillman, Tommy; Cheng, Mary H.; Chen, Qiang; Tang, Pei; Xu, Yan

2014-01-01

Pentameric ligand gated ion channels (pLGICs) are a family of structurally homologous cationic and anionic channels involved in neurotransmission. Cationic members of the pLGIC family are typically inhibited by general anesthetics, while anionic members are potentiated. GLIC is a prokaryotic cationic pLGIC and can be inhibited by clinical concentrations of general anesthetics. The introduction of three mutations, Y221A (Y–3′A), E222P (E–2′P) and N224R (N0′R), at the selectivity filter and one, A237T (A13′T), at the hydrophobic gate, converted GLIC to an anion channel. The mutated GLIC (GLIC4) became insensitive to the anesthetics propofol and etomidate as well as the channel blocker picrotoxin. Molecular dynamics (MD) simulations revealed changes in the structure and dynamics of GLIC4 in comparison to GLIC, particularly in the tilting angles of the pore-lining helix (TM2) that consequently resulted in different pore radius and hydration profiles. Propofol binding to an intra-subunit site of GLIC shifted the tilting angles of TM2 towards closure at the hydrophobic gate region, consistent with propofol inhibition of GLIC. In contrast, the pore of GLIC4 was much more resilient to perturbation from propofol binding. This study underscores the importance of pore dynamics and conformation to anesthetic effects on channel functions. PMID:22978431

Negative gating modulation by (R)-N-(benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphthylamine (NS8593) depends on residues in the inner pore vestibule: pharmacological evidence of deep-pore gating of K(Ca)2 channels.

PubMed

Jenkins, David Paul; Strøbæk, Dorte; Hougaard, Charlotte; Jensen, Marianne L; Hummel, Rene; Sørensen, Ulrik S; Christophersen, Palle; Wulff, Heike

2011-06-01

Acting as a negative gating modulator, (R)-N-(benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphthylamine (NS8593) shifts the apparent Ca(2+)-dependence of the small-conductance Ca(2+)-activated K(+) channels K(Ca)2.1-2.3 to higher Ca(2+) concentrations. Similar to the positive K(Ca) channel-gating modulators 1-ethyl-2-benzimidazolinone (1-EBIO) and cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methylpyrimidin-4-yl]-amine (CyPPA), the binding site for NS8593 has been assumed to be located in the C-terminal region, in which these channels interact with their Ca(2+) sensor calmodulin. However, by using a progressive chimeric approach, we were able to localize the site-of-action of NS8593 to the K(Ca)2 pore. For example, when we transferred the C terminus from the NS8593-insensitive intermediate-conductance K(Ca)3.1 channel to K(Ca)2.3, the chimeric channel remained as sensitive to NS8593 as wild-type K(Ca)2.3. In contrast, when we transferred the K(Ca)2.3 pore to K(Ca)3.1, the channel became sensitive to NS8593. Using site-directed mutagenesis, we subsequently identified two specific residues in the inner vestibule of K(Ca)2.3 (Ser507 and Ala532) that determined the effect of NS8593. Mutation of these residues to the corresponding residues in K(Ca)3.1 (Thr250 and Val275) made K(Ca)2.3 insensitive to NS8593, whereas introduction of serine and alanine into K(Ca)3.1 was sufficient to render this channel highly sensitive to NS8593. It is noteworthy that the same two residue positions have been found previously to mediate sensitivity of K(Ca)3.1 to clotrimazole and 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34). The location of Ser507 in the pore-loop near the selectivity filter and Ala532 in an adjacent position in S6 are within the region predicted to contain the K(Ca)2 channel gate. Hence, we propose that NS8593-mediated gating modulation occurs via interaction with gating structures at a position deep within the inner pore vestibule.

Mode shift of the voltage sensors in Shaker K+ channels is caused by energetic coupling to the pore domain

PubMed Central

Haddad, Georges A.

2011-01-01

The voltage sensors of voltage-gated ion channels undergo a conformational change upon depolarization of the membrane that leads to pore opening. This conformational change can be measured as gating currents and is thought to be transferred to the pore domain via an annealing of the covalent link between voltage sensor and pore (S4-S5 linker) and the C terminus of the pore domain (S6). Upon prolonged depolarizations, the voltage dependence of the charge movement shifts to more hyperpolarized potentials. This mode shift had been linked to C-type inactivation but has recently been suggested to be caused by a relaxation of the voltage sensor itself. In this study, we identified two ShakerIR mutations in the S4-S5 linker (I384N) and S6 (F484G) that, when mutated, completely uncouple voltage sensor movement from pore opening. Using these mutants, we show that the pore transfers energy onto the voltage sensor and that uncoupling the pore from the voltage sensor leads the voltage sensors to be activated at more negative potentials. This uncoupling also eliminates the mode shift occurring during prolonged depolarizations, indicating that the pore influences entry into the mode shift. Using voltage-clamp fluorometry, we identified that the slow conformational change of the S4 previously correlated with the mode shift disappears when uncoupling the pore. The effects can be explained by a mechanical load that is imposed upon the voltage sensors by the pore domain and allosterically modulates its conformation. Mode shift is caused by the stabilization of the open state but leads to a conformational change in the voltage sensor. PMID:21518834

Terahertz amplification in RTD-gated HEMTs with a grating-gate wave coupling topology

NASA Astrophysics Data System (ADS)

Condori Quispe, Hugo O.; Encomendero-Risco, Jimy J.; Xing, Huili Grace; Sensale-Rodriguez, Berardi

2016-08-01

We theoretically analyze the operation of a terahertz amplifier consisting of a resonant-tunneling-diode gated high-electron-mobility transistor (RTD-gated HEMT) in a grating-gate topology. In these devices, the key element enabling substantial power gain is the efficient coupling of terahertz waves into and out of plasmons in the RTD-gated HEMT channel, i.e., the gain medium, via the grating-gate itself, part of the active device, rather than by an external antenna structure as discussed in previous works, therefore potentially enabling terahertz amplification with associated power gains >40 dB.

A limited 4 Å radial displacement of the S4-S5 linker is sufficient for internal gate closing in Kv channels.

PubMed

Faure, Élise; Starek, Greg; McGuire, Hugo; Bernèche, Simon; Blunck, Rikard

2012-11-16

Voltage-gated ion channels are responsible for the generation of action potentials in our nervous system. Conformational rearrangements in their voltage sensor domains in response to changes of the membrane potential control pore opening and thus ion conduction. Crystal structures of the open channel in combination with a wealth of biophysical data and molecular dynamics simulations led to a consensus on the voltage sensor movement. However, the coupling between voltage sensor movement and pore opening, the electromechanical coupling, occurs at the cytosolic face of the channel, from where no structural information is available yet. In particular, the question how far the cytosolic pore gate has to close to prevent ion conduction remains controversial. In cells, spectroscopic methods are hindered because labeling of internal sites remains difficult, whereas liposomes or detergent solutions containing purified ion channels lack voltage control. Here, to overcome these problems, we controlled the state of the channel by varying the lipid environment. This way, we directly measured the position of the S4-S5 linker in both the open and the closed state of a prokaryotic Kv channel (KvAP) in a lipid environment using Lanthanide-based resonance energy transfer. We were able to reconstruct the movement of the covalent link between the voltage sensor and the pore domain and used this information as restraints for molecular dynamics simulations of the closed state structure. We found that a small decrease of the pore radius of about 3-4 Å is sufficient to prevent ion permeation through the pore.

Hydrophobic Gating of Ion Permeation in Magnesium Channel CorA.

PubMed

Neale, Chris; Chakrabarti, Nilmadhab; Pomorski, Pawel; Pai, Emil F; Pomès, Régis

2015-07-01

Ion channels catalyze ionic permeation across membranes via water-filled pores. To understand how changes in intracellular magnesium concentration regulate the influx of Mg2+ into cells, we examine early events in the relaxation of Mg2+ channel CorA toward its open state using massively-repeated molecular dynamics simulations conducted either with or without regulatory ions. The pore of CorA contains a 2-nm-long hydrophobic bottleneck which remained dehydrated in most simulations. However, rapid hydration or "wetting" events concurrent with small-amplitude fluctuations in pore diameter occurred spontaneously and reversibly. In the absence of regulatory ions, wetting transitions are more likely and include a wet state that is significantly more stable and more hydrated. The free energy profile for Mg2+ permeation presents a barrier whose magnitude is anticorrelated to pore diameter and the extent of hydrophobic hydration. These findings support an allosteric mechanism whereby wetting of a hydrophobic gate couples changes in intracellular magnesium concentration to the onset of ionic conduction.

Coupling mechanism in the gate and oscillator model of the SCN

NASA Astrophysics Data System (ADS)

Li, Ying; Liu, Zengrong

2016-09-01

In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus is considered as the master circadian pacemaker. The SCN is divided into two subgroups of gate and oscillator cells: the ventrolateral (VL) neurons, which receive the periodic light-dark (LD) signal, and the dorsomedial (DM) neurons, which are coupled to the VL cells. The fundamental question is how the individual cellular oscillators, expressing a wide range of periods, interact and assemble to create an integrated pacemaker that can govern behavioral and physiological rhythmicity and be reset by environmental light. The key is that the heterogeneous network formed by the cellular clocks within the SCN must synchronize to maintain timekeeping activity. Based on the structural and functional heterogeneity of the SCN, the authors bring forward a mathematical model including gate cells and oscillator cells with a wide range of periods. The gate neurons offer daily injection to oscillator neurons and the activation of gate is determined by the output of the oscillator neurons. In this model, the authors consider two kinds of coupling: interior coupling among the oscillator cells and exterior coupling from the gate cells to the oscillator cells. The authors mainly analyze the combined effects of these two kinds of coupling on the entrainment of the oscillator cells in the DM part. It is found that the interior coupling is conducive to entrainment, but a stronger coupling is not beneficial to entrainment. The gate mechanism in exterior coupling is more propitious to entrainment than continuous coupling. This study helps to understand collective circadian rhythm in the mammals.

A structural, functional, and computational analysis suggests pore flexibility as the base for the poor selectivity of CNG channels

PubMed Central

Napolitano, Luisa Maria Rosaria; Bisha, Ina; De March, Matteo; Marchesi, Arin; Arcangeletti, Manuel; Demitri, Nicola; Mazzolini, Monica; Rodriguez, Alex; Magistrato, Alessandra; Onesti, Silvia; Laio, Alessandro; Torre, Vincent

2015-01-01

Cyclic nucleotide-gated (CNG) ion channels, despite a significant homology with the highly selective K+ channels, do not discriminate among monovalent alkali cations and are permeable also to several organic cations. We combined electrophysiology, molecular dynamics (MD) simulations, and X-ray crystallography to demonstrate that the pore of CNG channels is highly flexible. When a CNG mimic is crystallized in the presence of a variety of monovalent cations, including Na+, Cs+, and dimethylammonium (DMA+), the side chain of Glu66 in the selectivity filter shows multiple conformations and the diameter of the pore changes significantly. MD simulations indicate that Glu66 and the prolines in the outer vestibule undergo large fluctuations, which are modulated by the ionic species and the voltage. This flexibility underlies the coupling between gating and permeation and the poor ionic selectivity of CNG channels. PMID:26100907

A structural, functional, and computational analysis suggests pore flexibility as the base for the poor selectivity of CNG channels.

PubMed

Napolitano, Luisa Maria Rosaria; Bisha, Ina; De March, Matteo; Marchesi, Arin; Arcangeletti, Manuel; Demitri, Nicola; Mazzolini, Monica; Rodriguez, Alex; Magistrato, Alessandra; Onesti, Silvia; Laio, Alessandro; Torre, Vincent

2015-07-07

Cyclic nucleotide-gated (CNG) ion channels, despite a significant homology with the highly selective K(+) channels, do not discriminate among monovalent alkali cations and are permeable also to several organic cations. We combined electrophysiology, molecular dynamics (MD) simulations, and X-ray crystallography to demonstrate that the pore of CNG channels is highly flexible. When a CNG mimic is crystallized in the presence of a variety of monovalent cations, including Na(+), Cs(+), and dimethylammonium (DMA(+)), the side chain of Glu66 in the selectivity filter shows multiple conformations and the diameter of the pore changes significantly. MD simulations indicate that Glu66 and the prolines in the outer vestibule undergo large fluctuations, which are modulated by the ionic species and the voltage. This flexibility underlies the coupling between gating and permeation and the poor ionic selectivity of CNG channels.

Molecular Dynamics Simulations of KirBac1.1 Mutants Reveal Global Gating Changes of Kir Channels.

PubMed

Linder, Tobias; Wang, Shizhen; Zangerl-Plessl, Eva-Maria; Nichols, Colin G; Stary-Weinzinger, Anna

2015-04-27

Prokaryotic inwardly rectifying (KirBac) potassium channels are homologous to mammalian Kir channels. Their activity is controlled by dynamical conformational changes that regulate ion flow through a central pore. Understanding the dynamical rearrangements of Kir channels during gating requires high-resolution structure information from channels crystallized in different conformations and insight into the transition steps, which are difficult to access experimentally. In this study, we use MD simulations on wild type KirBac1.1 and an activatory mutant to investigate activation gating of KirBac channels. Full atomistic MD simulations revealed that introducing glutamate in position 143 causes significant widening at the helix bundle crossing gate, enabling water flux into the cavity. Further, global rearrangements including a twisting motion as well as local rearrangements at the subunit interface in the cytoplasmic domain were observed. These structural rearrangements are similar to recently reported KirBac3.1 crystal structures in closed and open conformation, suggesting that our simulations capture major conformational changes during KirBac1.1 opening. In addition, an important role of protein-lipid interactions during gating was observed. Slide-helix and C-linker interactions with lipids were strengthened during activation gating.

Terahertz amplification in RTD-gated HEMTs with a grating-gate wave coupling topology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Condori Quispe, Hugo O.; Sensale-Rodriguez, Berardi; Encomendero-Risco, Jimy J.

2016-08-08

We theoretically analyze the operation of a terahertz amplifier consisting of a resonant-tunneling-diode gated high-electron-mobility transistor (RTD-gated HEMT) in a grating-gate topology. In these devices, the key element enabling substantial power gain is the efficient coupling of terahertz waves into and out of plasmons in the RTD-gated HEMT channel, i.e., the gain medium, via the grating-gate itself, part of the active device, rather than by an external antenna structure as discussed in previous works, therefore potentially enabling terahertz amplification with associated power gains >40 dB.

The isolated voltage sensing domain of the Shaker potassium channel forms a voltage-gated cation channel.

PubMed

Zhao, Juan; Blunck, Rikard

2016-10-06

Domains in macromolecular complexes are often considered structurally and functionally conserved while energetically coupled to each other. In the modular voltage-gated ion channels the central ion-conducting pore is surrounded by four voltage sensing domains (VSDs). Here, the energetic coupling is mediated by interactions between the S4-S5 linker, covalently linking the domains, and the proximal C-terminus. In order to characterize the intrinsic gating of the voltage sensing domain in the absence of the pore domain, the Shaker Kv channel was truncated after the fourth transmembrane helix S4 (Shaker-iVSD). Shaker-iVSD showed significantly altered gating kinetics and formed a cation-selective ion channel with a strong preference for protons. Ion conduction in Shaker-iVSD developed despite identical primary sequence, indicating an allosteric influence of the pore domain. Shaker-iVSD also displays pronounced 'relaxation'. Closing of the pore correlates with entry into relaxation suggesting that the two processes are energetically related.

Liquid-based gating mechanism with tunable multiphase selectivity and antifouling behaviour

NASA Astrophysics Data System (ADS)

Hou, Xu; Hu, Yuhang; Grinthal, Alison; Khan, Mughees; Aizenberg, Joanna

2015-03-01

Living organisms make extensive use of micro- and nanometre-sized pores as gatekeepers for controlling the movement of fluids, vapours and solids between complex environments. The ability of such pores to coordinate multiphase transport, in a highly selective and subtly triggered fashion and without clogging, has inspired interest in synthetic gated pores for applications ranging from fluid processing to 3D printing and lab-on-chip systems. But although specific gating and transport behaviours have been realized by precisely tailoring pore surface chemistries and pore geometries, a single system capable of controlling complex, selective multiphase transport has remained a distant prospect, and fouling is nearly inevitable. Here we introduce a gating mechanism that uses a capillary-stabilized liquid as a reversible, reconfigurable gate that fills and seals pores in the closed state, and creates a non-fouling, liquid-lined pore in the open state. Theoretical modelling and experiments demonstrate that for each transport substance, the gating threshold--the pressure needed to open the pores--can be rationally tuned over a wide pressure range. This enables us to realize in one system differential response profiles for a variety of liquids and gases, even letting liquids flow through the pore while preventing gas from escaping. These capabilities allow us to dynamically modulate gas-liquid sorting in a microfluidic flow and to separate a three-phase air-water-oil mixture, with the liquid lining ensuring sustained antifouling behaviour. Because the liquid gating strategy enables efficient long-term operation and can be applied to a variety of pore structures and membrane materials, and to micro- as well as macroscale fluid systems, we expect it to prove useful in a wide range of applications.

Liquid-based gating mechanism with tunable multiphase selectivity and antifouling behaviour.

PubMed

Hou, Xu; Hu, Yuhang; Grinthal, Alison; Khan, Mughees; Aizenberg, Joanna

2015-03-05

Living organisms make extensive use of micro- and nanometre-sized pores as gatekeepers for controlling the movement of fluids, vapours and solids between complex environments. The ability of such pores to coordinate multiphase transport, in a highly selective and subtly triggered fashion and without clogging, has inspired interest in synthetic gated pores for applications ranging from fluid processing to 3D printing and lab-on-chip systems. But although specific gating and transport behaviours have been realized by precisely tailoring pore surface chemistries and pore geometries, a single system capable of controlling complex, selective multiphase transport has remained a distant prospect, and fouling is nearly inevitable. Here we introduce a gating mechanism that uses a capillary-stabilized liquid as a reversible, reconfigurable gate that fills and seals pores in the closed state, and creates a non-fouling, liquid-lined pore in the open state. Theoretical modelling and experiments demonstrate that for each transport substance, the gating threshold-the pressure needed to open the pores-can be rationally tuned over a wide pressure range. This enables us to realize in one system differential response profiles for a variety of liquids and gases, even letting liquids flow through the pore while preventing gas from escaping. These capabilities allow us to dynamically modulate gas-liquid sorting in a microfluidic flow and to separate a three-phase air-water-oil mixture, with the liquid lining ensuring sustained antifouling behaviour. Because the liquid gating strategy enables efficient long-term operation and can be applied to a variety of pore structures and membrane materials, and to micro- as well as macroscale fluid systems, we expect it to prove useful in a wide range of applications.

Probing the Energy Landscape of Activation Gating of the Bacterial Potassium Channel KcsA

PubMed Central

Linder, Tobias; de Groot, Bert L.; Stary-Weinzinger, Anna

2013-01-01

The bacterial potassium channel KcsA, which has been crystallized in several conformations, offers an ideal model to investigate activation gating of ion channels. In this study, essential dynamics simulations are applied to obtain insights into the transition pathways and the energy profile of KcsA pore gating. In agreement with previous hypotheses, our simulations reveal a two phasic activation gating process. In the first phase, local structural rearrangements in TM2 are observed leading to an intermediate channel conformation, followed by large structural rearrangements leading to full opening of KcsA. Conformational changes of a highly conserved phenylalanine, F114, at the bundle crossing region are crucial for the transition from a closed to an intermediate state. 3.9 µs umbrella sampling calculations reveal that there are two well-defined energy barriers dividing closed, intermediate, and open channel states. In agreement with mutational studies, the closed state was found to be energetically more favorable compared to the open state. Further, the simulations provide new insights into the dynamical coupling effects of F103 between the activation gate and the selectivity filter. Investigations on individual subunits support cooperativity of subunits during activation gating. PMID:23658510

Ephaptic coupling rescues conduction failure in weakly coupled cardiac tissue with voltage-gated gap junctions

NASA Astrophysics Data System (ADS)

Weinberg, S. H.

2017-09-01

Electrical conduction in cardiac tissue is usually considered to be primarily facilitated by gap junctions, providing a pathway between the intracellular spaces of neighboring cells. However, recent studies have highlighted the role of coupling via extracellular electric fields, also known as ephaptic coupling, particularly in the setting of reduced gap junction expression. Further, in the setting of reduced gap junctional coupling, voltage-dependent gating of gap junctions, an oft-neglected biophysical property in computational studies, produces a positive feedback that promotes conduction failure. We hypothesized that ephaptic coupling can break the positive feedback loop and rescue conduction failure in weakly coupled cardiac tissue. In a computational tissue model incorporating voltage-gated gap junctions and ephaptic coupling, we demonstrate that ephaptic coupling can rescue conduction failure in weakly coupled tissue. Further, ephaptic coupling increased conduction velocity in weakly coupled tissue, and importantly, reduced the minimum gap junctional coupling necessary for conduction, most prominently at fast pacing rates. Finally, we find that, although neglecting gap junction voltage-gating results in negligible differences in well coupled tissue, more significant differences occur in weakly coupled tissue, greatly underestimating the minimal gap junctional coupling that can maintain conduction. Our study suggests that ephaptic coupling plays a conduction-preserving role, particularly at rapid heart rates.

Fast Dynamical Decoupling of the Mølmer-Sørensen Entangling Gate.

PubMed

Manovitz, Tom; Rotem, Amit; Shaniv, Ravid; Cohen, Itsik; Shapira, Yotam; Akerman, Nitzan; Retzker, Alex; Ozeri, Roee

2017-12-01

Engineering entanglement between quantum systems often involves coupling through a bosonic mediator, which should be disentangled from the systems at the operation's end. The quality of such an operation is generally limited by environmental and control noise. One of the prime techniques for suppressing noise is by dynamical decoupling, where one actively applies pulses at a rate that is faster than the typical time scale of the noise. However, for boson-mediated gates, current dynamical decoupling schemes require executing the pulses only when the boson and the quantum systems are disentangled. This restriction implies an increase of the gate time by a factor of sqrt[N], with N being the number of pulses applied. Here we propose and realize a method that enables dynamical decoupling in a boson-mediated system where the pulses can be applied while spin-boson entanglement persists, resulting in an increase in time that is at most a factor of π/2, independently of the number of pulses applied. We experimentally demonstrate the robustness of our entangling gate with fast dynamical decoupling to σ_{z} noise using ions in a Paul trap.

Liquid-based gating mechanism with tunable multiphase selectivity and antifouling behaviour

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hou, X; Hu, YH; Grinthal, A

Living organisms make extensive use of micro- and nanometre-sized pores as gatekeepers for controlling the movement of fluids, vapours and solids between complex environments. The ability of such pores to coordinate multiphase transport, in a highly selective and subtly triggered fashion and without clogging, has inspired interest in synthetic gated pores for applications ranging from fluid processing to 3D printing and lab-on-chip systems(1-10). But although specific gating and transport behaviours have been realized by precisely tailoring pore surface chemistries and pore geometries(6,11-17), a single system capable of controlling complex, selective multiphase transport has remained a distant prospect, and fouling ismore » nearly inevitable(11,12). Here we introduce a gating mechanism that uses a capillary-stabilized liquid as a reversible, reconfigurable gate that fills and seals pores in the closed state, and creates a non-fouling, liquid-lined pore in the open state. Theoretical modelling and experiments demonstrate that for each transport substance, the gating threshold-the pressure needed to open the pores-can be rationally tuned over a wide pressure range. This enables us to realize in one system differential response profiles for a variety of liquids and gases, even letting liquids flow through the pore while preventing gas from escaping. These capabilities allow us to dynamically modulate gas-liquid sorting in a microfluidic flow and to separate a three-phase air-water-oil mixture, with the liquid lining ensuring sustained antifouling behaviour. Because the liquid gating strategy enables efficient long-term operation and can be applied to a variety of pore structures and membrane materials, and to micro- as well as macroscale fluid systems, we expect it to prove useful in a wide range of applications.« less

Hydrophobic Gating of Ion Permeation in Magnesium Channel CorA

PubMed Central

Neale, Chris; Chakrabarti, Nilmadhab; Pomorski, Pawel; Pai, Emil F.; Pomès, Régis

2015-01-01

Ion channels catalyze ionic permeation across membranes via water-filled pores. To understand how changes in intracellular magnesium concentration regulate the influx of Mg2+ into cells, we examine early events in the relaxation of Mg2+ channel CorA toward its open state using massively-repeated molecular dynamics simulations conducted either with or without regulatory ions. The pore of CorA contains a 2-nm-long hydrophobic bottleneck which remained dehydrated in most simulations. However, rapid hydration or “wetting” events concurrent with small-amplitude fluctuations in pore diameter occurred spontaneously and reversibly. In the absence of regulatory ions, wetting transitions are more likely and include a wet state that is significantly more stable and more hydrated. The free energy profile for Mg2+ permeation presents a barrier whose magnitude is anticorrelated to pore diameter and the extent of hydrophobic hydration. These findings support an allosteric mechanism whereby wetting of a hydrophobic gate couples changes in intracellular magnesium concentration to the onset of ionic conduction. PMID:26181442

Liquid-based gating mechanism with tunable multiphase selectivity and antifouling behaviour

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hou, Xu; Hu, Yuhang; Grinthal, Alison

Living organisms make extensive use of micro- and nanometre-sized pores as gatekeepers for controlling the movement of fluids, vapours and solids between complex environments. In addition, the ability of such pores to coordinate multiphase transport, in a highly selective and subtly triggered fashion and without clogging, has inspired interest in synthetic gated pores for applications ranging from fluid processing to 3D printing and lab-on-chip systems 1-10.But although specific gating and transport behaviours have been realized by precisely tailoring pore surface chemistries and pore geometries 6,11–17, a single system capable of controlling complex, selective multiphase transport has remained a distant prospect,more » and fouling is nearly inevitable.Here we introduce a gating mechanism that uses a capillary-stabilized liquid as a reversible, reconfigurable gate that fills and seals pores in the closed state, and creates a non-fouling, liquid-lined pore in the open state.Theoretical modelling and experiments demonstrate that for each transport substance, the gating threshold—the pressure needed to open the pores—can be rationally tuned over a wide pressure range. This enables us to realize in one system differential response profiles for a variety of liquids and gases, even letting liquids flow through the pore while preventing gas from escaping.These capabilities allow us to dynamically modulate gas–liquid sorting in a microfluidic flow and to separate a three-phase air water–oil mixture, with the liquid lining ensuring sustained antifouling behaviour. Because the liquid gating strategy enables efficient long-term operation and can be applied to a variety of pore structures and membrane materials, and to micro- as well as macroscale fluid systems, we expect it to prove useful in a wide range of applications.« less

Liquid-based gating mechanism with tunable multiphase selectivity and antifouling behaviour

DOE PAGES

Hou, Xu; Hu, Yuhang; Grinthal, Alison; ...

2015-03-04

Living organisms make extensive use of micro- and nanometre-sized pores as gatekeepers for controlling the movement of fluids, vapours and solids between complex environments. In addition, the ability of such pores to coordinate multiphase transport, in a highly selective and subtly triggered fashion and without clogging, has inspired interest in synthetic gated pores for applications ranging from fluid processing to 3D printing and lab-on-chip systems 1-10.But although specific gating and transport behaviours have been realized by precisely tailoring pore surface chemistries and pore geometries 6,11–17, a single system capable of controlling complex, selective multiphase transport has remained a distant prospect,more » and fouling is nearly inevitable.Here we introduce a gating mechanism that uses a capillary-stabilized liquid as a reversible, reconfigurable gate that fills and seals pores in the closed state, and creates a non-fouling, liquid-lined pore in the open state.Theoretical modelling and experiments demonstrate that for each transport substance, the gating threshold—the pressure needed to open the pores—can be rationally tuned over a wide pressure range. This enables us to realize in one system differential response profiles for a variety of liquids and gases, even letting liquids flow through the pore while preventing gas from escaping.These capabilities allow us to dynamically modulate gas–liquid sorting in a microfluidic flow and to separate a three-phase air water–oil mixture, with the liquid lining ensuring sustained antifouling behaviour. Because the liquid gating strategy enables efficient long-term operation and can be applied to a variety of pore structures and membrane materials, and to micro- as well as macroscale fluid systems, we expect it to prove useful in a wide range of applications.« less

The isolated voltage sensing domain of the Shaker potassium channel forms a voltage-gated cation channel

PubMed Central

Zhao, Juan; Blunck, Rikard

2016-01-01

Domains in macromolecular complexes are often considered structurally and functionally conserved while energetically coupled to each other. In the modular voltage-gated ion channels the central ion-conducting pore is surrounded by four voltage sensing domains (VSDs). Here, the energetic coupling is mediated by interactions between the S4-S5 linker, covalently linking the domains, and the proximal C-terminus. In order to characterize the intrinsic gating of the voltage sensing domain in the absence of the pore domain, the Shaker Kv channel was truncated after the fourth transmembrane helix S4 (Shaker-iVSD). Shaker-iVSD showed significantly altered gating kinetics and formed a cation-selective ion channel with a strong preference for protons. Ion conduction in Shaker-iVSD developed despite identical primary sequence, indicating an allosteric influence of the pore domain. Shaker-iVSD also displays pronounced 'relaxation'. Closing of the pore correlates with entry into relaxation suggesting that the two processes are energetically related. DOI: http://dx.doi.org/10.7554/eLife.18130.001 PMID:27710769

Visualization of Membrane Pore in Live Cells Reveals a Dynamic-Pore Theory Governing Fusion and Endocytosis.

PubMed

Shin, Wonchul; Ge, Lihao; Arpino, Gianvito; Villarreal, Seth A; Hamid, Edaeni; Liu, Huisheng; Zhao, Wei-Dong; Wen, Peter J; Chiang, Hsueh-Cheng; Wu, Ling-Gang

2018-05-03

Fusion is thought to open a pore to release vesicular cargoes vital for many biological processes, including exocytosis, intracellular trafficking, fertilization, and viral entry. However, fusion pores have not been observed and thus proved in live cells. Its regulatory mechanisms and functions remain poorly understood. With super-resolution STED microscopy, we observed dynamic fusion pore behaviors in live (neuroendocrine) cells, including opening, expansion, constriction, and closure, where pore size may vary between 0 and 490 nm within 26 milliseconds to seconds (vesicle size: 180-720 nm). These pore dynamics crucially determine the efficiency of vesicular cargo release and vesicle retrieval. They are generated by competition between pore expansion and constriction. Pharmacology and mutation experiments suggest that expansion and constriction are mediated by F-actin-dependent membrane tension and calcium/dynamin, respectively. These findings provide the missing live-cell evidence, proving the fusion-pore hypothesis, and establish a live-cell dynamic-pore theory accounting for fusion, fission, and their regulation. Published by Elsevier Inc.

Structural Changes Fundamental to Gating of the Cystic Fibrosis Transmembrane Conductance Regulator Anion Channel Pore.

PubMed

Linsdell, Paul

2017-01-01

Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), an epithelial cell anion channel. Potentiator drugs used in the treatment of cystic fibrosis act on the channel to increase overall channel function, by increasing the stability of its open state and/or decreasing the stability of its closed state. The structure of the channel in either the open state or the closed state is not currently known. However, changes in the conformation of the protein as it transitions between these two states have been studied using functional investigation and molecular modeling techniques. This review summarizes our current understanding of the architecture of the transmembrane channel pore that controls the movement of chloride and other small anions, both in the open state and in the closed state. Evidence for different kinds of changes in the conformation of the pore as it transitions between open and closed states is described, as well as the mechanisms by which these conformational changes might be controlled to regulate normal channel gating. The ways that key conformational changes might be targeted by small compounds to influence overall CFTR activity are also discussed. Understanding the changes in pore structure that might be manipulated by such small compounds is key to the development of novel therapeutic strategies for the treatment of cystic fibrosis.

Structural model of FeoB, the iron transporter from Pseudomonas aeruginosa, predicts a cysteine lined, GTP-gated pore

PubMed Central

Seyedmohammad, Saeed; Fuentealba, Natalia Alveal; Marriott, Robert A.J.; Goetze, Tom A.; Edwardson, J. Michael; Barrera, Nelson P.; Venter, Henrietta

2016-01-01

Iron is essential for the survival and virulence of pathogenic bacteria. The FeoB transporter allows the bacterial cell to acquire ferrous iron from its environment, making it an excellent drug target in intractable pathogens. The protein consists of an N-terminal GTP-binding domain and a C-terminal membrane domain. Despite the availability of X-ray crystal structures of the N-terminal domain, many aspects of the structure and function of FeoB remain unclear, such as the structure of the membrane domain, the oligomeric state of the protein, the molecular mechanism of iron transport, and how this is coupled to GTP hydrolysis at the N-terminal domain. In the present study, we describe the first homology model of FeoB. Due to the lack of sequence homology between FeoB and other transporters, the structures of four different proteins were used as templates to generate the homology model of full-length FeoB, which predicts a trimeric structure. We confirmed this trimeric structure by both blue-native-PAGE (BN-PAGE) and AFM. According to our model, the membrane domain of the trimeric protein forms a central pore lined by highly conserved cysteine residues. This pore aligns with a central pore in the N-terminal GTPase domain (G-domain) lined by aspartate residues. Biochemical analysis of FeoB from Pseudomonas aeruginosa further reveals a putative iron sensor domain that could connect GTP binding/hydrolysis to the opening of the pore. These results indicate that FeoB might not act as a transporter, but rather as a GTP-gated channel. PMID:26934982

One-microsecond molecular dynamics simulation of channel gating in a nicotinic receptor homologue

PubMed Central

Nury, Hugues; Poitevin, Frédéric; Van Renterghem, Catherine; Changeux, Jean-Pierre; Corringer, Pierre-Jean; Delarue, Marc; Baaden, Marc

2010-01-01

Recently discovered bacterial homologues of eukaryotic pentameric ligand-gated ion channels, such as the Gloeobacter violaceus receptor (GLIC), are increasingly used as structural and functional models of signal transduction in the nervous system. Here we present a one-microsecond-long molecular dynamics simulation of the GLIC channel pH stimulated gating mechanism. The crystal structure of GLIC obtained at acidic pH in an open-channel form is equilibrated in a membrane environment and then instantly set to neutral pH. The simulation shows a channel closure that rapidly takes place at the level of the hydrophobic furrow and a progressively increasing quaternary twist. Two major events are captured during the simulation. They are initiated by local but large fluctuations in the pore, taking place at the top of the M2 helix, followed by a global tertiary relaxation. The two-step transition of the first subunit starts within the first 50 ns of the simulation and is followed at 450 ns by its immediate neighbor in the pentamer, which proceeds with a similar scenario. This observation suggests a possible two-step domino-like tertiary mechanism that takes place between adjacent subunits. In addition, the dynamical properties of GLIC described here offer an interpretation of the paradoxical properties of a permeable A13′F mutant whose crystal structure determined at 3.15 Å shows a pore too narrow to conduct ions. PMID:20308576

The pore-lining region of shaker voltage-gated potassium channels: comparison of beta-barrel and alpha-helix bundle models.

PubMed Central

Kerr, I D; Sansom, M S

1997-01-01

Although there is a large body of site-directed mutagenesis data that identify the pore-lining sequence of the voltage-gated potassium channel, the structure of this region remains unknown. We have interpreted the available biochemical data as a set of topological and orientational restraints and employed these restraints to produce molecular models of the potassium channel pore region, H5. The H5 sequence has been modeled either as a tetramer of membrane-spanning beta-hairpins, thus producing an eight-stranded beta-barrel, or as a tetramer of incompletely membrane-spanning alpha-helical hairpins, thus producing an eight-staved alpha-helix bundle. In total, restraints-directed modeling has produced 40 different configurations of the beta-barrel model, each configuration comprising an ensemble of 20 structures, and 24 different configurations of the alpha-helix bundle model, each comprising an ensemble of 24 structures. Thus, over 1300 model structures for H5 have been generated. Configurations have been ranked on the basis of their predicted pore properties and on the extent of their agreement with the biochemical data. This ranking is employed to identify particular configurations of H5 that may be explored further as models of the pore-lining region of the voltage-gated potassium channel pore. Images FIGURE 7 FIGURE 12 PMID:9251779

Dynamic pore-scale network model (PNM) of water imbibition in porous media

NASA Astrophysics Data System (ADS)

Li, J.; McDougall, S. R.; Sorbie, K. S.

2017-09-01

A dynamic pore-scale network model is presented which simulates 2-phase oil/water displacement during water imbibition by explicitly modelling intra-pore dynamic bulk and film flows using a simple local model. A new dynamic switching parameter, λ, is proposed within this model which is able to simulate the competition between local capillary forces and viscous forces over a very wide range of flow conditions. This quantity (λ) determines the primary pore filling mechanism during imbibition; i.e. whether the dominant force is (i) piston-like displacement under viscous forces, (ii) film swelling/collapse and snap-off due to capillary forces, or (iii) some intermediate local combination of both mechanisms. A series of 2D dynamic pore network simulations is presented which shows that the λ-model can satisfactorily reproduce and explain different filling regimes of water imbibition over a wide range of capillary numbers (Ca) and viscosity ratios (M). These imbibition regimes are more complex than those presented under drainage by (Lenormand et al. (1983)), since they are determined by a wider group of control parameters. Our simulations show that there is a coupling between viscous and capillary forces that is much less important in drainage. The effects of viscosity ratio during imbibition are apparent even under conditions of very slow flow (low Ca)-displacements that would normally be expected to be completely capillary dominated. This occurs as a result of the wetting films having a much greater relative mobility in the higher M cases (e.g. M = 10) thus leading to a higher level of film swelling/snap-off, resulting in local oil cluster bypassing and trapping, and hence a poorer oil recovery. This deeper coupled viscous mechanism is the underlying reason why the microscopic displacement efficiency is lower for higher M cases in water imbibition processes. Additional results are presented from the dynamic model on the corresponding effluent fractional flows (fw

C-terminal modulatory domain controls coupling of voltage-sensing to pore opening in Cav1.3 L-type Ca(2+) channels.

PubMed

Lieb, Andreas; Ortner, Nadine; Striessnig, Jörg

2014-04-01

Activity of voltage-gated Cav1.3 L-type Ca(2+) channels is required for proper hearing as well as sinoatrial node and brain function. This critically depends on their negative activation voltage range, which is further fine-tuned by alternative splicing. Shorter variants miss a C-terminal regulatory domain (CTM), which allows them to activate at even more negative potentials than C-terminally long-splice variants. It is at present unclear whether this is due to an increased voltage sensitivity of the Cav1.3 voltage-sensing domain, or an enhanced coupling of voltage-sensor conformational changes to the subsequent opening of the activation gate. We studied the voltage-dependence of voltage-sensor charge movement (QON-V) and of current activation (ICa-V) of the long (Cav1.3L) and a short Cav1.3 splice variant (Cav1.342A) expressed in tsA-201 cells using whole cell patch-clamp. Charge movement (QON) of Cav1.3L displayed a much steeper voltage-dependence and a more negative half-maximal activation voltage than Cav1.2 and Cav3.1. However, a significantly higher fraction of the total charge had to move for activation of Cav1.3 half-maximal conductance (Cav1.3: 68%; Cav1.2: 52%; Cav3.1: 22%). This indicated a weaker coupling of Cav1.3 voltage-sensor charge movement to pore opening. However, the coupling efficiency was strengthened in the absence of the CTM in Cav1.342A, thereby shifting ICa-V by 7.2 mV to potentials that were more negative without changing QON-V. We independently show that the presence of intracellular organic cations (such as n-methyl-D-glucamine) induces a pronounced negative shift of QON-V and a more negative activation of ICa-V of all three channels. These findings illustrate that the voltage sensors of Cav1.3 channels respond more sensitively to depolarization than those of Cav1.2 or Cav3.1. Weak coupling of voltage sensing to pore opening is enhanced in the absence of the CTM, allowing short Cav1.342A splice variants to activate at lower voltages

Gating Topology of the Proton-Coupled Oligopeptide Symporters

PubMed Central

Fowler, Philip W.; Orwick-Rydmark, Marcella; Radestock, Sebastian; Solcan, Nicolae; Dijkman, Patricia M.; Lyons, Joseph A.; Kwok, Jane; Caffrey, Martin; Watts, Anthony; Forrest, Lucy R.; Newstead, Simon

2015-01-01

Summary Proton-coupled oligopeptide transporters belong to the major facilitator superfamily (MFS) of membrane transporters. Recent crystal structures suggest the MFS fold facilitates transport through rearrangement of their two six-helix bundles around a central ligand binding site; how this is achieved, however, is poorly understood. Using modeling, molecular dynamics, crystallography, functional assays, and site-directed spin labeling combined with double electron-electron resonance (DEER) spectroscopy, we present a detailed study of the transport dynamics of two bacterial oligopeptide transporters, PepTSo and PepTSt. Our results identify several salt bridges that stabilize outward-facing conformations and we show that, for all the current structures of MFS transporters, the first two helices of each of the four inverted-topology repeat units form half of either the periplasmic or cytoplasmic gate and that these function cooperatively in a scissor-like motion to control access to the peptide binding site during transport. PMID:25651061

The First Extracellular Linker Is Important for Several Aspects of the Gating Mechanism of Human TRPA1 Channel

PubMed Central

Marsakova, Lenka; Barvik, Ivan; Zima, Vlastimil; Zimova, Lucie; Vlachova, Viktorie

2017-01-01

Transient receptor potential ankyrin 1 (TRPA1) is an excitatory ion channel involved in pain, inflammation and itching. This channel gates in response to many irritant and proalgesic agents, and can be modulated by calcium and depolarizing voltage. While the closed-state structure of TRPA1 has been recently resolved, also having its open state is essential for understanding how this channel works. Here we use molecular dynamics simulations combined with electrophysiological measurements and systematic mutagenesis to predict and explore the conformational changes coupled to the expansion of the presumptive channel's lower gate. We show that, upon opening, the upper part of the sensor module approaches the pore domain of an adjacent subunit and the conformational dynamics of the first extracellular flexible loop may govern the voltage-dependence of multimodal gating, thereby serving to stabilize the open state of the channel. These results are generally important in understanding the structure and function of TRPA1 and offer new insights into the gating mechanism of TRPA1 and related channels. PMID:28197074

Conformational changes of an ion-channel during gating and emerging electrophysiologic properties: Application of a computational approach to cardiac Kv7.1.

PubMed

Nekouzadeh, Ali; Rudy, Yoram

2016-01-01

Ion channels are the "building blocks" of the excitation process in excitable tissues. Despite advances in determining their molecular structure, understanding the relationship between channel protein structure and electrical excitation remains a challenge. The Kv7.1 potassium channel is an important determinant of the cardiac action potential and its adaptation to rate changes. It is subject to beta adrenergic regulation, and many mutations in the channel protein are associated with the arrhythmic long QT syndrome. In this theoretical study, we use a novel computational approach to simulate the conformational changes that Kv7.1 undergoes during activation gating and compute the resulting electrophysiologic function in terms of single-channel and macroscopic currents. We generated all possible conformations of the S4-S5 linker that couples the S3-S4 complex (voltage sensor domain, VSD) to the pore, and all associated conformations of VSD and the pore (S6). Analysis of these conformations revealed that VSD-to-pore mechanical coupling during activation gating involves outward translation of the voltage sensor, accompanied by a translation away from the pore and clockwise twist. These motions cause pore opening by moving the S4-S5 linker upward and away from the pore, providing space for the S6 tails to move away from each other. Single channel records, computed from the simulated motion trajectories during gating, have stochastic properties similar to experimentally recorded traces. Macroscopic current through an ensemble of channels displays two key properties of Kv7.1: an initial delay of activation and fast inactivation. The simulations suggest a molecular mechanism for fast inactivation; a large twist of the VSD following its outward translation results in movement of the base of the S4-S5 linker toward the pore, eliminating open pore conformations to cause inactivation. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Impact of pore size variability and network coupling on electrokinetic transport in porous media

NASA Astrophysics Data System (ADS)

Alizadeh, Shima; Bazant, Martin Z.; Mani, Ali

2016-11-01

We have developed and validated an efficient and robust computational model to study the coupled fluid and ion transport through electrokinetic porous media, which are exposed to external gradients of pressure, electric potential, and concentration. In our approach a porous media is modeled as a network of many pores through which the transport is described by the coupled Poisson-Nernst-Planck-Stokes equations. When the pore sizes are random, the interactions between various modes of transport may provoke complexities such as concentration polarization shocks and internal flow circulations. These phenomena impact mixing and transport in various systems including deionization and filtration systems, supercapacitors, and lab-on-a-chip devices. In this work, we present simulations of massive networks of pores and we demonstrate the impact of pore size variation, and pore-pore coupling on the overall electrokinetic transport in porous media.

Coupling root architecture and pore network modeling - an attempt towards better understanding root-soil interactions

NASA Astrophysics Data System (ADS)

Leitner, Daniel; Bodner, Gernot; Raoof, Amir

2013-04-01

, but also improve the description of the rooting environment. Until now there have been no attempts to couple root architecture and pore network models. In our work we present a first attempt to join both types of models using the root architecture model of Leitner et al., (2010) and a pore network model presented by Raoof et al. (2010). The two main objectives of coupling both models are: (i) Representing the effect of root induced biopores on flow and transport processes: For this purpose a fixed root architecture created by the root model is superimposed as a secondary root induced pore network to the primary soil network, thus influencing the final pore topology in the network generation. (ii) Representing the influence of pre-existing pores on root branching: Using a given network of (rigid) pores, the root architecture model allocates its root axes into these preexisting pores as preferential growth paths with thereby shape the final root architecture. The main objective of our study is to reveal the potential of using a pore scale description of the plant growth medium for an improved representation of interaction processes at the interface of root and soil. References Raoof, A., Hassanizadeh, S.M. 2010. A New Method for Generating Pore-Network Models. Transp. Porous Med. 81, 391-407. Leitner, D, Klepsch, S., Bodner, G., Schnepf, S. 2010. A dynamic root system growth model based on L-Systems. Tropisms and coupling to nutrient uptake from soil. Plant Soil 332, 177-192.

Voltage-Gated Potassium Channels: A Structural Examination of Selectivity and Gating

PubMed Central

Kim, Dorothy M.; Nimigean, Crina M.

2016-01-01

Voltage-gated potassium channels play a fundamental role in the generation and propagation of the action potential. The discovery of these channels began with predictions made by early pioneers, and has culminated in their extensive functional and structural characterization by electrophysiological, spectroscopic, and crystallographic studies. With the aid of a variety of crystal structures of these channels, a highly detailed picture emerges of how the voltage-sensing domain reports changes in the membrane electric field and couples this to conformational changes in the activation gate. In addition, high-resolution structural and functional studies of K+ channel pores, such as KcsA and MthK, offer a comprehensive picture on how selectivity is achieved in K+ channels. Here, we illustrate the remarkable features of voltage-gated potassium channels and explain the mechanisms used by these machines with experimental data. PMID:27141052

Universal photonic quantum gates assisted by ancilla diamond nitrogen-vacancy centers coupled to resonators

NASA Astrophysics Data System (ADS)

Wei, Hai-Rui; Long, Gui Lu

2015-03-01

We propose two compact, economic, and scalable schemes for implementing optical controlled-phase-flip and controlled-controlled-phase-flip gates by using the input-output process of a single-sided cavity strongly coupled to a single nitrogen-vacancy-center defect in diamond. Additional photonic qubits, necessary for procedures based on the parity-check measurement or controlled-path and merging gates, are not employed in our schemes. In the controlled-path gate, the paths of the target photon are conditionally controlled by the control photon, and these two paths can be merged back into one by using a merging gate. Only one half-wave plate is employed in our scheme for the controlled-phase-flip gate. Compared with the conventional synthesis procedures for constructing a controlled-controlled-phase-flip gate, the cost of which is two controlled-path gates and two merging gates, or six controlled-not gates, our scheme is more compact and simpler. Our schemes could be performed with a high fidelity and high efficiency with current achievable experimental techniques.

Quantum memory and gates using a Λ -type quantum emitter coupled to a chiral waveguide

NASA Astrophysics Data System (ADS)

Li, Tao; Miranowicz, Adam; Hu, Xuedong; Xia, Keyu; Nori, Franco

2018-06-01

By coupling a Λ -type quantum emitter to a chiral waveguide, in which the polarization of a photon is locked to its propagation direction, we propose a controllable photon-emitter interface for quantum networks. We show that this chiral system enables the swap gate and a hybrid-entangling gate between the emitter and a flying single photon. It also allows deterministic storage and retrieval of single-photon states with high fidelities and efficiencies. In short, this chirally coupled emitter-photon interface can be a critical building block toward a large-scale quantum network.

Extraction of the gate capacitance coupling coefficient in floating gate non-volatile memories: Statistical study of the effect of mismatching between floating gate memory and reference transistor in dummy cell extraction methods

NASA Astrophysics Data System (ADS)

Rafhay, Quentin; Beug, M. Florian; Duane, Russell

2007-04-01

This paper presents an experimental comparison of dummy cell extraction methods of the gate capacitance coupling coefficient for floating gate non-volatile memory structures from different geometries and technologies. These results show the significant influence of mismatching floating gate devices and reference transistors on the extraction of the gate capacitance coupling coefficient. In addition, it demonstrates the accuracy of the new bulk bias dummy cell extraction method and the importance of the β function, introduced recently in [Duane R, Beug F, Mathewson A. Novel capacitance coupling coefficient measurement methodology for floating gate non-volatile memory devices. IEEE Electr Dev Lett 2005;26(7):507-9], to determine matching pairs of floating gate memory and reference transistor.

Analytical Calculation of Mutual Information between Weakly Coupled Poisson-Spiking Neurons in Models of Dynamically Gated Communication.

PubMed

Cannon, Jonathan

2017-01-01

Mutual information is a commonly used measure of communication between neurons, but little theory exists describing the relationship between mutual information and the parameters of the underlying neuronal interaction. Such a theory could help us understand how specific physiological changes affect the capacity of neurons to synaptically communicate, and, in particular, they could help us characterize the mechanisms by which neuronal dynamics gate the flow of information in the brain. Here we study a pair of linear-nonlinear-Poisson neurons coupled by a weak synapse. We derive an analytical expression describing the mutual information between their spike trains in terms of synapse strength, neuronal activation function, the time course of postsynaptic currents, and the time course of the background input received by the two neurons. This expression allows mutual information calculations that would otherwise be computationally intractable. We use this expression to analytically explore the interaction of excitation, information transmission, and the convexity of the activation function. Then, using this expression to quantify mutual information in simulations, we illustrate the information-gating effects of neural oscillations and oscillatory coherence, which may either increase or decrease the mutual information across the synapse depending on parameters. Finally, we show analytically that our results can quantitatively describe the selection of one information pathway over another when multiple sending neurons project weakly to a single receiving neuron.

Temperature-sensitive gating of TRPV1 channel as probed by atomistic simulations of its trans- and juxtamembrane domains

NASA Astrophysics Data System (ADS)

Chugunov, Anton O.; Volynsky, Pavel E.; Krylov, Nikolay A.; Nolde, Dmitry E.; Efremov, Roman G.

2016-09-01

Heat-activated transient receptor potential channel TRPV1 is one of the most studied eukaryotic proteins involved in temperature sensation. Upon heating, it exhibits rapid reversible pore gating, which depolarizes neurons and generates action potentials. Underlying molecular details of such effects in the pore region of TRPV1 is of a crucial importance to control temperature responses of the organism. Despite the spatial structure of the channel in both open (O) and closed (C) states is known, microscopic nature of channel gating and mechanism of thermal sensitivity are still poorly understood. In this work, we used unrestrained atomistic molecular dynamics simulations of TRPV1 (without N- and C-terminal cytoplasmic domains) embedded into explicit lipid bilayer in its O- and C-states. We found that the pore domain with its neighboring loops undergoes large temperature-dependent conformational transitions in an asymmetric way, when fragments of only one monomer move with large amplitude, freeing the pore upon heating. Such an asymmetrical gating looks rather biologically relevant because it is faster and more reliable than traditionally proposed “iris-like” symmetric scheme of channel opening. Analysis of structural, dynamic, and hydrophobic organization of the pore domain revealed entropy growth upon TRPV1 gating, which is in line with current concepts of thermal sensitivity.

Photo-switchable tweezers illuminate pore-opening motions of an ATP-gated P2X ion channel

PubMed Central

Habermacher, Chloé; Martz, Adeline; Calimet, Nicolas; Lemoine, Damien; Peverini, Laurie; Specht, Alexandre; Cecchini, Marco; Grutter, Thomas

2016-01-01

P2X receptors function by opening a transmembrane pore in response to extracellular ATP. Recent crystal structures solved in apo and ATP-bound states revealed molecular motions of the extracellular domain following agonist binding. However, the mechanism of pore opening still remains controversial. Here we use photo-switchable cross-linkers as ‘molecular tweezers’ to monitor a series of inter-residue distances in the transmembrane domain of the P2X2 receptor during activation. These experimentally based structural constraints combined with computational studies provide high-resolution models of the channel in the open and closed states. We show that the extent of the outer pore expansion is significantly reduced compared to the ATP-bound structure. Our data further reveal that the inner and outer ends of adjacent pore-lining helices come closer during opening, likely through a hinge-bending motion. These results provide new insight into the gating mechanism of P2X receptors and establish a versatile strategy applicable to other membrane proteins. DOI: http://dx.doi.org/10.7554/eLife.11050.001 PMID:26808983

PIP2-dependent coupling is prominent in Kv7.1 due to weakened interactions between S4-S5 and S6

NASA Astrophysics Data System (ADS)

Kasimova, Marina A.; Zaydman, Mark A.; Cui, Jianmin; Tarek, Mounir

2015-01-01

Among critical aspects of voltage-gated potassium (Kv) channels' functioning is the effective communication between their two composing domains, the voltage sensor (VSD) and the pore. This communication, called coupling, might be transmitted directly through interactions between these domains and, as recently proposed, indirectly through interactions with phosphatidylinositol-4,5-bisphosphate (PIP2), a minor lipid of the inner plasma membrane leaflet. Here, we show how the two components of coupling, mediated by protein-protein or protein-lipid interactions, both contribute in the Kv7.1 functioning. On the one hand, using molecular dynamics simulations, we identified a Kv7.1 PIP2 binding site that involves residues playing a key role in PIP2-dependent coupling. On the other hand, combined theoretical and experimental approaches have shown that the direct interaction between the segments of the VSD (S4-S5) and the pore (S6) is weakened by electrostatic repulsion. Finally, we conclude that due to weakened protein-protein interactions, the PIP2-dependent coupling is especially prominent in Kv7.1.

Pore-pressure sensitivities to dynamic strains: observations in active tectonic regions

USGS Publications Warehouse

Barbour, Andrew J.

2015-01-01

Triggered seismicity arising from dynamic stresses is often explained by the Mohr-Coulomb failure criterion, where elevated pore pressures reduce the effective strength of faults in fluid-saturated rock. The seismic response of a fluid-rock system naturally depends on its hydro-mechanical properties, but accurately assessing how pore-fluid pressure responds to applied stress over large scales in situ remains a challenging task; hence, spatial variations in response are not well understood, especially around active faults. Here I analyze previously unutilized records of dynamic strain and pore-pressure from regional and teleseismic earthquakes at Plate Boundary Observatory (PBO) stations from 2006 through 2012 to investigate variations in response along the Pacific/North American tectonic plate boundary. I find robust scaling-response coefficients between excess pore pressure and dynamic strain at each station that are spatially correlated: around the San Andreas and San Jacinto fault systems, the response is lowest in regions of the crust undergoing the highest rates of secular shear strain. PBO stations in the Parkfield instrument cluster are at comparable distances to the San Andreas fault (SAF), and spatial variations there follow patterns in dextral creep rates along the fault, with the highest response in the actively creeping section, which is consistent with a narrowing zone of strain accumulation seen in geodetic velocity profiles. At stations in the San Juan Bautista (SJB) and Anza instrument clusters, the response depends non-linearly on the inverse fault-perpendicular distance, with the response decreasing towards the fault; the SJB cluster is at the northern transition from creeping-to-locked behavior along the SAF, where creep rates are at moderate to low levels, and the Anza cluster is around the San Jacinto fault, where to date there have been no statistically significant creep rates observed at the surface. These results suggest that the strength

Isolated pores dissected from human two-pore channel 2 are functional

PubMed Central

Penny, Christopher J.; Rahman, Taufiq; Sula, Altin; Miles, Andrew J.; Wallace, B. A.; Patel, Sandip

2016-01-01

Multi-domain voltage-gated ion channels appear to have evolved through sequential rounds of intragenic duplication from a primordial one-domain precursor. Whereas modularity within one-domain symmetrical channels is established, little is known about the roles of individual regions within more complex asymmetrical channels where the domains have undergone substantial divergence. Here we isolated and characterised both of the divergent pore regions from human TPC2, a two-domain channel that holds a key intermediate position in the evolution of voltage-gated ion channels. In HeLa cells, each pore localised to the ER and caused Ca2+ depletion, whereas an ER-targeted pore mutated at a residue that inactivates full-length TPC2 did not. Additionally, one of the pores expressed at high levels in E. coli. When purified, it formed a stable, folded tetramer. Liposomes reconstituted with the pore supported Ca2+ and Na+ uptake that was inhibited by known blockers of full-length channels. Computational modelling of the pore corroborated cationic permeability and drug interaction. Therefore, despite divergence, both pores are constitutively active in the absence of their partners and retain several properties of the wild-type pore. Such symmetrical ‘pore-only’ proteins derived from divergent channel domains may therefore provide tractable tools for probing the functional architecture of complex ion channels. PMID:27941820

Isolated pores dissected from human two-pore channel 2 are functional.

PubMed

Penny, Christopher J; Rahman, Taufiq; Sula, Altin; Miles, Andrew J; Wallace, B A; Patel, Sandip

2016-12-12

Multi-domain voltage-gated ion channels appear to have evolved through sequential rounds of intragenic duplication from a primordial one-domain precursor. Whereas modularity within one-domain symmetrical channels is established, little is known about the roles of individual regions within more complex asymmetrical channels where the domains have undergone substantial divergence. Here we isolated and characterised both of the divergent pore regions from human TPC2, a two-domain channel that holds a key intermediate position in the evolution of voltage-gated ion channels. In HeLa cells, each pore localised to the ER and caused Ca 2+ depletion, whereas an ER-targeted pore mutated at a residue that inactivates full-length TPC2 did not. Additionally, one of the pores expressed at high levels in E. coli. When purified, it formed a stable, folded tetramer. Liposomes reconstituted with the pore supported Ca 2+ and Na + uptake that was inhibited by known blockers of full-length channels. Computational modelling of the pore corroborated cationic permeability and drug interaction. Therefore, despite divergence, both pores are constitutively active in the absence of their partners and retain several properties of the wild-type pore. Such symmetrical 'pore-only' proteins derived from divergent channel domains may therefore provide tractable tools for probing the functional architecture of complex ion channels.

Optimized cross-resonance gate for coupled transmon systems

NASA Astrophysics Data System (ADS)

Kirchhoff, Susanna; Keßler, Torsten; Liebermann, Per J.; Assémat, Elie; Machnes, Shai; Motzoi, Felix; Wilhelm, Frank K.

2018-04-01

The cross-resonance (CR) gate is an entangling gate for fixed-frequency superconducting qubits. While being simple and extensible, it is comparatively slow, at 160 ns, and thus of limited fidelity due to on-going incoherent processes. Using two different optimal control algorithms, we estimate the quantum speed limit for a controlled-not cnot gate in this system to be 10 ns, indicating a potential for great improvements. We show that the ability to approach this limit depends strongly on the choice of ansatz used to describe optimized control pulses and limitations placed on their complexity. Using a piecewise-constant ansatz, with a single carrier and bandwidth constraints, we identify an experimentally feasible 70-ns pulse shape. Further, an ansatz based on the two dominant frequencies involved in the optimal control problem allows for an optimal solution more than twice as fast again, at under 30 ns, with smooth features and limited complexity. This is twice as fast as gate realizations using tunable-frequency, resonantly coupled qubits. Compared to current CR-gate implementations, we project our scheme will provide a sixfold speed-up and thus a sixfold reduction in fidelity loss due to incoherent effects.

Liquid gating elastomeric porous system with dynamically controllable gas/liquid transport.

PubMed

Sheng, Zhizhi; Wang, Honglong; Tang, Yongliang; Wang, Miao; Huang, Lizhi; Min, Lingli; Meng, Haiqiang; Chen, Songyue; Jiang, Lei; Hou, Xu

2018-02-01

The development of membrane technology is central to fields ranging from resource harvesting to medicine, but the existing designs are unable to handle the complex sorting of multiphase substances required for many systems. Especially, the dynamic multiphase transport and separation under a steady-state applied pressure have great benefits for membrane science, but have not been realized at present. Moreover, the incorporation of precisely dynamic control with avoidance of contamination of membranes remains elusive. We show a versatile strategy for creating elastomeric microporous membrane-based systems that can finely control and dynamically modulate the sorting of a wide range of gases and liquids under a steady-state applied pressure, nearly eliminate fouling, and can be easily applied over many size scales, pressures, and environments. Experiments and theoretical calculation demonstrate the stability of our system and the tunability of the critical pressure. Dynamic transport of gas and liquid can be achieved through our gating interfacial design and the controllable pores' deformation without changing the applied pressure. Therefore, we believe that this system will bring new opportunities for many applications, such as gas-involved chemical reactions, fuel cells, multiphase separation, multiphase flow, multiphase microreactors, colloidal particle synthesis, and sizing nano/microparticles.

Tunable inter-qubit coupling as a resource for gate based quantum computing with superconducting circuits

NASA Astrophysics Data System (ADS)

Chiaro, B.; Neill, C.; Chen, Z.; Dunsworth, A.; Foxen, B.; Quintana, C.; Wenner, J.; Martinis, J. M.; Google Quantum Hardware Team

Fast, high fidelity two qubit gates are an essential requirement of a quantum processor. In this talk, we discuss how the tunable coupling of the gmon architecture provides a pathway for an improved two qubit controlled-Z gate. The maximum inter-qubit coupling strength gmax = 60 MHz is sufficient for fast adiabatic two qubit gates to be performed as quickly as single qubit gates, reducing dephasing errors. Additionally, the ability to turn the coupling off allows all qubits to idle at low magnetic flux sensitivity, further reducing susceptibility to noise. However, the flexibility that this platform offers comes at the expense of increased control complexity. We describe our strategy for addressing the control challenges of the gmon architecture and show experimental progress toward fast, high fidelity controlled-Z gates with gmon qubits.

Investigation of Coupled model of Pore network and Continuum in shale gas

NASA Astrophysics Data System (ADS)

Cao, G.; Lin, M.

2016-12-01

Flow in shale spanning over many scales, makes the majority of conventional treatment methods disabled. For effectively simulating, a coupled model of pore-scale and continuum-scale was proposed in this paper. Based on the SEM image, we decompose organic-rich-shale into two subdomains: kerogen and inorganic matrix. In kerogen, the nanoscale pore-network is the main storage space and migration pathway so that the molecular phenomena (slip and diffusive transport) is significant. Whereas, inorganic matrix, with relatively large pores and micro fractures, the flow is approximate to Darcy. We use pore-scale network models (PNM) to represent kerogen and continuum-scale models (FVM or FEM) to represent matrix. Finite element mortars are employed to couple pore- and continuum-scale models by enforcing continuity of pressures and fluxes at shared boundary interfaces. In our method, the process in the coupled model is described by pressure square equation, and uses Dirichlet boundary conditions. We discuss several problems: the optimal element number of mortar faces, two categories boundary faces of pore network, the difference between 2D and 3D models, and the difference between continuum models FVM and FEM in mortars. We conclude that: (1) too coarse mesh in mortars will decrease the accuracy, while too fine mesh will lead to an ill-condition even singular system, the optimal element number is depended on boundary pores and nodes number. (2) pore network models are adjacent to two different mortar faces (PNM to PNM, PNM to continuum model), incidental repeated mortar nodes must be deleted. (3) 3D models can be replaced by 2D models under certain condition. (4) FVM is more convenient than FEM, for its simplicity in assigning interface nodes pressure and calculating interface fluxes. This work is supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB10020302), the 973 Program (2014CB239004), the Key Instrument Developing Project of the

Voltage-gated sodium channel β subunits: The power outside the pore in brain development and disease.

PubMed

Hull, Jacob M; Isom, Lori L

2018-04-01

Voltage gated sodium channels (VGSCs) were first identified in terms of their role in the upstroke of the action potential. The underlying proteins were later identified as saxitoxin and scorpion toxin receptors consisting of α and β subunits. We now know that VGSCs are heterotrimeric complexes consisting of a single pore forming α subunit joined by two β subunits; a noncovalently linked β1 or β3 and a covalently linked β2 or β4 subunit. VGSC α subunits contain all the machinery necessary for channel cell surface expression, ion conduction, voltage sensing, gating, and inactivation, in one central, polytopic, transmembrane protein. VGSC β subunits are more than simple accessories to α subunits. In the more than two decades since the original cloning of β1, our knowledge of their roles in physiology and pathophysiology has expanded immensely. VGSC β subunits are multifunctional. They confer unique gating mechanisms, regulate cellular excitability, affect brain development, confer distinct channel pharmacology, and have functions that are independent of the α subunits. The vast array of functions of these proteins stems from their special station in the channelome: being the only known constituents that are cell adhesion and intra/extracellular signaling molecules in addition to being part of channel complexes. This functional trifecta and how it goes awry demonstrates the power outside the pore in ion channel signaling complexes, broadening the term channelopathy beyond defects in ion conduction. This article is part of the Special Issue entitled 'Channelopathies.' Copyright © 2017 Elsevier Ltd. All rights reserved.

Structural changes in the cytoplasmic pore of the Kir1.1 channel during pHi-gating probed by FRET.

PubMed

Lee, Jay-Ron; Shieh, Ru-Chi

2009-03-06

Kir1.1 channels are important in maintaining K+ homeostasis in the kidney. Intracellular acidification reversibly closes the Kir1.1 channel and thus decreases K+ secretion. In this study, we used Foster resonance energy transfer (FRET) to determine whether the conformation of the cytoplasmic pore changes in response to intracellular pH (pHi)-gating in Kir1.1 channels fused with enhanced cyan fluorescent protein (ECFP) and enhanced yellow fluorescent protein (EYFP) (ECFP-Kir1.1-EYFP). Because the fluorescence intensities of ECFP and EYFP were affected at pHi < 7.4 where pHi-gating occurs in the ECFP-Kir1.1-EYFP construct, we examined the FRET efficiencies of an ECFP-S219R-EYFP mutant, which is completed closed at pHi 7.4 and open at pHi 10.0. FRET efficiency was increased from 25% to 40% when the pHi was decreased from 10.0 to 7.4. These results suggest that the conformation of the cytoplasmic pore in the Kir1.1 channel changes in response to pHi gating such that the N- and C-termini move apart from each other at pHi 7.4, when the channel is open.

Dynamic acousto-optic control of a strongly coupled photonic molecule

PubMed Central

Kapfinger, Stephan; Reichert, Thorsten; Lichtmannecker, Stefan; Müller, Kai; Finley, Jonathan J.; Wixforth, Achim; Kaniber, Michael; Krenner, Hubert J.

2015-01-01

Strongly confined photonic modes can couple to quantum emitters and mechanical excitations. To harness the full potential in quantum photonic circuits, interactions between different constituents have to be precisely and dynamically controlled. Here, a prototypical coupled element, a photonic molecule defined in a photonic crystal membrane, is controlled by a radio frequency surface acoustic wave. The sound wave is tailored to deliberately switch on and off the bond of the photonic molecule on sub-nanosecond timescales. In time-resolved experiments, the acousto-optically controllable coupling is directly observed as clear anticrossings between the two nanophotonic modes. The coupling strength is determined directly from the experimental data. Both the time dependence of the tuning and the inter-cavity coupling strength are found to be in excellent agreement with numerical calculations. The demonstrated mechanical technique can be directly applied for dynamic quantum gate operations in state-of-the-art-coupled nanophotonic, quantum cavity electrodynamic and optomechanical systems. PMID:26436203

Source-Coupled, N-Channel, JFET-Based Digital Logic Gate Structure Using Resistive Level Shifters

NASA Technical Reports Server (NTRS)

Krasowski, Michael J.

2011-01-01

A circuit topography is used to create usable, digital logic gates using N (negatively doped) channel junction field effect transistors (JFETs), load resistors, level shifting resistors, and supply rails whose values are based on the DC parametric distributions of these JFETs. This method has direct application to the current state-of-the-art in high-temperature (300 to 500 C and higher) silicon carbide (SiC) device production, and defines an adaptation to the logic gate described in U.S. Patent 7,688,117 in that, by removing the level shifter from the output of the gate structure described in the patent (and applying it to the input of the same gate), a source-coupled gate topography is created. This structure allows for the construction AND/OR (sum of products) arrays that use far fewer transistors and resistors than the same array as constructed from the gates described in the aforementioned patent. This plays a central role when large multiplexer constructs are necessary; for example, as in the construction of memory. This innovation moves the resistive level shifter from the output of the basic gate structure to the front as if the input is now configured as what would be the output of the preceding gate, wherein the output is the two level shifting resistors. The output of this innovation can now be realized as the lone follower transistor with its source node as the gate output. Additionally, one may leave intact the resistive level shifter on the new gate topography. A source-coupled to direct-coupled logic translator will be the result.

Structure of the voltage-gated K⁺ channel Eag1 reveals an alternative voltage sensing mechanism.

PubMed

Whicher, Jonathan R; MacKinnon, Roderick

2016-08-12

Voltage-gated potassium (K(v)) channels are gated by the movement of the transmembrane voltage sensor, which is coupled, through the helical S4-S5 linker, to the potassium pore. We determined the single-particle cryo-electron microscopy structure of mammalian K(v)10.1, or Eag1, bound to the channel inhibitor calmodulin, at 3.78 angstrom resolution. Unlike previous K(v) structures, the S4-S5 linker of Eag1 is a five-residue loop and the transmembrane segments are not domain swapped, which suggest an alternative mechanism of voltage-dependent gating. Additionally, the structure and position of the S4-S5 linker allow calmodulin to bind to the intracellular domains and to close the potassium pore, independent of voltage-sensor position. The structure reveals an alternative gating mechanism for K(v) channels and provides a template to further understand the gating properties of Eag1 and related channels. Copyright © 2016, American Association for the Advancement of Science.

Molecular basis of the interaction between gating modifier spider toxins and the voltage sensor of voltage-gated ion channels

NASA Astrophysics Data System (ADS)

Lau, Carus H. Y.; King, Glenn F.; Mobli, Mehdi

2016-09-01

Voltage-sensor domains (VSDs) are modular transmembrane domains of voltage-gated ion channels that respond to changes in membrane potential by undergoing conformational changes that are coupled to gating of the ion-conducting pore. Most spider-venom peptides function as gating modifiers by binding to the VSDs of voltage-gated channels and trapping them in a closed or open state. To understand the molecular basis underlying this mode of action, we used nuclear magnetic resonance to delineate the atomic details of the interaction between the VSD of the voltage-gated potassium channel KvAP and the spider-venom peptide VSTx1. Our data reveal that the toxin interacts with residues in an aqueous cleft formed between the extracellular S1-S2 and S3-S4 loops of the VSD whilst maintaining lipid interactions in the gaps formed between the S1-S4 and S2-S3 helices. The resulting network of interactions increases the energetic barrier to the conformational changes required for channel gating, and we propose that this is the mechanism by which gating modifier toxins inhibit voltage-gated ion channels.

Gating mechanism of Kv11.1 (hERG) K+ channels without covalent connection between voltage sensor and pore domains.

PubMed

de la Peña, Pilar; Domínguez, Pedro; Barros, Francisco

2018-03-01

Kv11.1 (hERG, KCNH2) is a voltage-gated potassium channel crucial in setting the cardiac rhythm and the electrical behaviour of several non-cardiac cell types. Voltage-dependent gating of Kv11.1 can be reconstructed from non-covalently linked voltage sensing and pore modules (split channels), challenging classical views of voltage-dependent channel activation based on a S4-S5 linker acting as a rigid mechanical lever to open the gate. Progressive displacement of the split position from the end to the beginning of the S4-S5 linker induces an increasing negative shift in activation voltage dependence, a reduced z g value and a more negative ΔG 0 for current activation, an almost complete abolition of the activation time course sigmoid shape and a slowing of the voltage-dependent deactivation. Channels disconnected at the S4-S5 linker near the S4 helix show a destabilization of the closed state(s). Furthermore, the isochronal ion current mode shift magnitude is clearly reduced in the different splits. Interestingly, the progressive modifications of voltage dependence activation gating by changing the split position are accompanied by a shift in the voltage-dependent availability to a methanethiosulfonate reagent of a Cys introduced at the upper S4 helix. Our data demonstrate for the first time that alterations in the covalent connection between the voltage sensor and the pore domains impact on the structural reorganizations of the voltage sensor domain. Also, they support the hypothesis that the S4-S5 linker integrates signals coming from other cytoplasmic domains that constitute either an important component or a crucial regulator of the gating machinery in Kv11.1 and other KCNH channels.

Numerical simulation on hydromechanical coupling in porous media adopting three-dimensional pore-scale model.

PubMed

Liu, Jianjun; Song, Rui; Cui, Mengmeng

2014-01-01

A novel approach of simulating hydromechanical coupling in pore-scale models of porous media is presented in this paper. Parameters of the sandstone samples, such as the stress-strain curve, Poisson's ratio, and permeability under different pore pressure and confining pressure, are tested in laboratory scale. The micro-CT scanner is employed to scan the samples for three-dimensional images, as input to construct the model. Accordingly, four physical models possessing the same pore and rock matrix characteristics as the natural sandstones are developed. Based on the micro-CT images, the three-dimensional finite element models of both rock matrix and pore space are established by MIMICS and ICEM software platform. Navier-Stokes equation and elastic constitutive equation are used as the mathematical model for simulation. A hydromechanical coupling analysis in pore-scale finite element model of porous media is simulated by ANSYS and CFX software. Hereby, permeability of sandstone samples under different pore pressure and confining pressure has been predicted. The simulation results agree well with the benchmark data. Through reproducing its stress state underground, the prediction accuracy of the porous rock permeability in pore-scale simulation is promoted. Consequently, the effects of pore pressure and confining pressure on permeability are revealed from the microscopic view.

Numerical Simulation on Hydromechanical Coupling in Porous Media Adopting Three-Dimensional Pore-Scale Model

PubMed Central

Liu, Jianjun; Song, Rui; Cui, Mengmeng

2014-01-01

A novel approach of simulating hydromechanical coupling in pore-scale models of porous media is presented in this paper. Parameters of the sandstone samples, such as the stress-strain curve, Poisson's ratio, and permeability under different pore pressure and confining pressure, are tested in laboratory scale. The micro-CT scanner is employed to scan the samples for three-dimensional images, as input to construct the model. Accordingly, four physical models possessing the same pore and rock matrix characteristics as the natural sandstones are developed. Based on the micro-CT images, the three-dimensional finite element models of both rock matrix and pore space are established by MIMICS and ICEM software platform. Navier-Stokes equation and elastic constitutive equation are used as the mathematical model for simulation. A hydromechanical coupling analysis in pore-scale finite element model of porous media is simulated by ANSYS and CFX software. Hereby, permeability of sandstone samples under different pore pressure and confining pressure has been predicted. The simulation results agree well with the benchmark data. Through reproducing its stress state underground, the prediction accuracy of the porous rock permeability in pore-scale simulation is promoted. Consequently, the effects of pore pressure and confining pressure on permeability are revealed from the microscopic view. PMID:24955384

Facile fabrication of highly controllable gating systems based on the combination of inverse opal structure and dynamic covalent chemistry.

PubMed

Wang, Chen; Yang, Haowei; Tian, Li; Wang, Shiqiang; Gao, Ning; Zhang, Wanlin; Wang, Peng; Yin, Xianpeng; Li, Guangtao

2017-06-01

A three-dimensional (3D) inverse opal with periodic and porous structures has shown great potential for applications not only in optics and optoelectronics, but also in functional membranes. In this work, the benzaldehyde group was initially introduced into a 3D nanoporous inverse opal, serving as a platform for fabricating functional membranes. By employing the dynamic covalent approach, a highly controllable gating system was facilely fabricated to achieve modulable and reversible transport features. It was found that the physical/chemical properties and pore size of the gating system could easily be regulated through post-modification with amines. As a demonstration, the gated nanopores were modified with three kinds of amines to control the wettability, surface charge and nanopore size which in turn was exploited to achieve selective mass transport, including hydrophobic molecules, cations and anions, and the transport with respect to the physical steric hindrance. In particular, the gating system showed extraordinary reversibility and could recover to its pristine state by simply changing pH values. Due to the unlimited variety provided by the Schiff base reaction, the inverse opal described here exhibits a significant extendibility and could be easily post-modified with stimuli-responsive molecules for special purposes. Furthermore, this work can be extended to employ other dynamic covalent routes, for example Diels-Alder, ester exchange and disulfide exchange-based routes.

Structure of a eukaryotic cyclic nucleotide-gated channel

PubMed Central

Li, Minghui; Zhou, Xiaoyuan; Wang, Shu; Michailidis, Ioannis; Gong, Ye; Su, Deyuan; Li, Huan; Li, Xueming; Yang, Jian

2018-01-01

Summary Cyclic nucleotide-gated (CNG) channels are essential for vision and olfaction. They belong to the voltage-gated ion channel superfamily but their activities are controlled by intracellular cyclic nucleotides instead of transmembrane voltage. Here we report a 3.5 Å-resolution single-particle electron cryomicroscopy structure of a CNG channel from C. elegans in the cGMP-bound open state. The channel has an unusual voltage-sensor-like domain (VSLD), accounting for its deficient voltage dependence. A C-terminal linker connecting S6 and the cyclic nucleotide-binding domain interacts directly with both the VSLD and pore domain, forming a gating ring that couples conformational changes triggered by cyclic nucleotide binding to the gate. The selectivity filter is lined by the carboxylate side chains of a functionally important glutamate and three rings of backbone carbonyls. This structure provides a new framework for understanding mechanisms of ion permeation, gating and channelopathy of CNG channels and cyclic nucleotide modulation of related channels. PMID:28099415

Two separate interfaces between the voltage sensor and pore are required for the function of voltage-dependent K(+) channels.

PubMed

Lee, Seok-Yong; Banerjee, Anirban; MacKinnon, Roderick

2009-03-03

Voltage-dependent K(+) (Kv) channels gate open in response to the membrane voltage. To further our understanding of how cell membrane voltage regulates the opening of a Kv channel, we have studied the protein interfaces that attach the voltage-sensor domains to the pore. In the crystal structure, three physical interfaces exist. Only two of these consist of amino acids that are co-evolved across the interface between voltage sensor and pore according to statistical coupling analysis of 360 Kv channel sequences. A first co-evolved interface is formed by the S4-S5 linkers (one from each of four voltage sensors), which form a cuff surrounding the S6-lined pore opening at the intracellular surface. The crystal structure and published mutational studies support the hypothesis that the S4-S5 linkers convert voltage-sensor motions directly into gate opening and closing. A second co-evolved interface forms a small contact surface between S1 of the voltage sensor and the pore helix near the extracellular surface. We demonstrate through mutagenesis that this interface is necessary for the function and/or structure of two different Kv channels. This second interface is well positioned to act as a second anchor point between the voltage sensor and the pore, thus allowing efficient transmission of conformational changes to the pore's gate.

Ion-Gated Gas Separation through Porous Graphene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tian, Ziqi; Mahurin, Shannon M.; Dai, Sheng

Porous graphene holds great promise as an atom-thin, high-permeance membrane for gas separation, but to precisely control the pore size at three to five angstroms proves challenging. Here we propose an ion-gated graphene membrane comprising a monolayer of ionic liquid coated porous graphene to dynamically modulate the pore size to achieve selective gas separation. This approach enables the otherwise non-selective large pores on the order of 1 nm in size to be selective for gases whose diameters range from three to four angstroms. We show from molecular dynamics simulations that CO 2, N 2 and CH 4 all can permeatemore » through a 1-nm pore in graphene without any selectivity. But when a monolayer of [emim][BF 4] is deposited on the porous graphene, CO 2 has much higher permeance than the other two gases. We find that the anion dynamically modulates the pore size by hovering above the pore and provides affinity for CO 2 while the larger cation (which cannot go through the pore) holds the anion in place via electrostatic attraction. This composite membrane is especially promising for CO 2/CH 4 separation, with a CO 2/CH 4 selectivity of about 42 and CO 2 permeance ~105 GPU (gas permeation unit). We further demonstrate that selectivity and permeance can be tuned by the anion size. The present work points toward a promising direction of using the atom-thin ionic-liquid/porous-graphene hybrid membrane for high-permeance, selective gas separation that allows a greater flexibility in substrate pore size control.« less

Ion-Gated Gas Separation through Porous Graphene

DOE PAGES

Tian, Ziqi; Mahurin, Shannon M.; Dai, Sheng; ...

2017-02-10

Porous graphene holds great promise as an atom-thin, high-permeance membrane for gas separation, but to precisely control the pore size at three to five angstroms proves challenging. Here we propose an ion-gated graphene membrane comprising a monolayer of ionic liquid coated porous graphene to dynamically modulate the pore size to achieve selective gas separation. This approach enables the otherwise non-selective large pores on the order of 1 nm in size to be selective for gases whose diameters range from three to four angstroms. We show from molecular dynamics simulations that CO 2, N 2 and CH 4 all can permeatemore » through a 1-nm pore in graphene without any selectivity. But when a monolayer of [emim][BF 4] is deposited on the porous graphene, CO 2 has much higher permeance than the other two gases. We find that the anion dynamically modulates the pore size by hovering above the pore and provides affinity for CO 2 while the larger cation (which cannot go through the pore) holds the anion in place via electrostatic attraction. This composite membrane is especially promising for CO 2/CH 4 separation, with a CO 2/CH 4 selectivity of about 42 and CO 2 permeance ~105 GPU (gas permeation unit). We further demonstrate that selectivity and permeance can be tuned by the anion size. The present work points toward a promising direction of using the atom-thin ionic-liquid/porous-graphene hybrid membrane for high-permeance, selective gas separation that allows a greater flexibility in substrate pore size control.« less

Pore-scale dynamics of enzyme adsorption, swelling and reactive dissolution determine sugar yield in hemicellulose hydrolysis for biofuel production

PubMed Central

Dutta, Sajal Kanti; Chakraborty, Saikat

2016-01-01

Hemicelluloses are the earth’s second most abundant structural polymers, found in lignocellulosic biomass. Efficient enzymatic depolymerization of xylans by cleaving their β-(1 → 4)-glycosidic bonds to produce soluble sugars is instrumental to the cost-effective production of liquid biofuels. Here we show that the multi-scale two-phase process of enzymatic hydrolysis of amorphous hemicelluloses is dominated by its smallest scale–the pores. In the crucial first five hours, two to fourfold swelling of the xylan particles allow the enzymes to enter the pores and undergo rapid non-equilibrium adsorption on the pore surface before they hydrolyze the solid polymers, albeit non-competitively inhibited by the products xylose and xylobiose. Rapid pore-scale reactive dissolution increases the solid carbohydrate’s porosity to 80–90%. This tightly coupled experimental and theoretical study quantifies the complex temporal dynamics of the transport and reaction processes coupled across scales and phases to show that this unique pore-scale phenomenon can be exploited to accelerate the depolymerization of hemicelluloses to monomeric sugars in the first 5–6 h. We find that an ‘optimal substrate loading’ of 5 mg/ml (above which substrate inhibition sets in) accelerates non-equilibrium enzyme adsorption and solid hemicellulose depolymerization at the pore-scale, which contributes three-quarters of the soluble sugars produced for bio-alcohol fermentation. PMID:27905534

Pore-scale dynamics of enzyme adsorption, swelling and reactive dissolution determine sugar yield in hemicellulose hydrolysis for biofuel production

NASA Astrophysics Data System (ADS)

Dutta, Sajal Kanti; Chakraborty, Saikat

2016-12-01

Hemicelluloses are the earth’s second most abundant structural polymers, found in lignocellulosic biomass. Efficient enzymatic depolymerization of xylans by cleaving their β-(1 → 4)-glycosidic bonds to produce soluble sugars is instrumental to the cost-effective production of liquid biofuels. Here we show that the multi-scale two-phase process of enzymatic hydrolysis of amorphous hemicelluloses is dominated by its smallest scale-the pores. In the crucial first five hours, two to fourfold swelling of the xylan particles allow the enzymes to enter the pores and undergo rapid non-equilibrium adsorption on the pore surface before they hydrolyze the solid polymers, albeit non-competitively inhibited by the products xylose and xylobiose. Rapid pore-scale reactive dissolution increases the solid carbohydrate’s porosity to 80-90%. This tightly coupled experimental and theoretical study quantifies the complex temporal dynamics of the transport and reaction processes coupled across scales and phases to show that this unique pore-scale phenomenon can be exploited to accelerate the depolymerization of hemicelluloses to monomeric sugars in the first 5-6 h. We find that an ‘optimal substrate loading’ of 5 mg/ml (above which substrate inhibition sets in) accelerates non-equilibrium enzyme adsorption and solid hemicellulose depolymerization at the pore-scale, which contributes three-quarters of the soluble sugars produced for bio-alcohol fermentation.

Voltage-dependent gating of KCNH potassium channels lacking a covalent link between voltage-sensing and pore domains

PubMed Central

Lörinczi, Éva; Gómez-Posada, Juan Camilo; de la Peña, Pilar; Tomczak, Adam P.; Fernández-Trillo, Jorge; Leipscher, Ulrike; Stühmer, Walter; Barros, Francisco; Pardo, Luis A.

2015-01-01

Voltage-gated channels open paths for ion permeation upon changes in membrane potential, but how voltage changes are coupled to gating is not entirely understood. Two modules can be recognized in voltage-gated potassium channels, one responsible for voltage sensing (transmembrane segments S1 to S4), the other for permeation (S5 and S6). It is generally assumed that the conversion of a conformational change in the voltage sensor into channel gating occurs through the intracellular S4–S5 linker that provides physical continuity between the two regions. Using the pathophysiologically relevant KCNH family, we show that truncated proteins interrupted at, or lacking the S4–S5 linker produce voltage-gated channels in a heterologous model that recapitulate both the voltage-sensing and permeation properties of the complete protein. These observations indicate that voltage sensing by the S4 segment is transduced to the channel gate in the absence of physical continuity between the modules. PMID:25818916

Voltage-dependent gating of KCNH potassium channels lacking a covalent link between voltage-sensing and pore domains.

PubMed

Lörinczi, Éva; Gómez-Posada, Juan Camilo; de la Peña, Pilar; Tomczak, Adam P; Fernández-Trillo, Jorge; Leipscher, Ulrike; Stühmer, Walter; Barros, Francisco; Pardo, Luis A

2015-03-30

Voltage-gated channels open paths for ion permeation upon changes in membrane potential, but how voltage changes are coupled to gating is not entirely understood. Two modules can be recognized in voltage-gated potassium channels, one responsible for voltage sensing (transmembrane segments S1 to S4), the other for permeation (S5 and S6). It is generally assumed that the conversion of a conformational change in the voltage sensor into channel gating occurs through the intracellular S4-S5 linker that provides physical continuity between the two regions. Using the pathophysiologically relevant KCNH family, we show that truncated proteins interrupted at, or lacking the S4-S5 linker produce voltage-gated channels in a heterologous model that recapitulate both the voltage-sensing and permeation properties of the complete protein. These observations indicate that voltage sensing by the S4 segment is transduced to the channel gate in the absence of physical continuity between the modules.

Voltage-dependent gating of KCNH potassium channels lacking a covalent link between voltage-sensing and pore domains

NASA Astrophysics Data System (ADS)

Lörinczi, Éva; Gómez-Posada, Juan Camilo; de La Peña, Pilar; Tomczak, Adam P.; Fernández-Trillo, Jorge; Leipscher, Ulrike; Stühmer, Walter; Barros, Francisco; Pardo, Luis A.

2015-03-01

Voltage-gated channels open paths for ion permeation upon changes in membrane potential, but how voltage changes are coupled to gating is not entirely understood. Two modules can be recognized in voltage-gated potassium channels, one responsible for voltage sensing (transmembrane segments S1 to S4), the other for permeation (S5 and S6). It is generally assumed that the conversion of a conformational change in the voltage sensor into channel gating occurs through the intracellular S4-S5 linker that provides physical continuity between the two regions. Using the pathophysiologically relevant KCNH family, we show that truncated proteins interrupted at, or lacking the S4-S5 linker produce voltage-gated channels in a heterologous model that recapitulate both the voltage-sensing and permeation properties of the complete protein. These observations indicate that voltage sensing by the S4 segment is transduced to the channel gate in the absence of physical continuity between the modules.

Exterior Site Occupancy Infers Chloride-Induced Proton Gating in a Prokaryotic Homolog of the ClC Chloride Channel

PubMed Central

Bostick, David L.; Berkowitz, Max L.

2004-01-01

The ClC family of anion channels mediates the efficient, selective permeation of Cl− across the biological membranes of living cells under the driving force of an electrochemical gradient. In some eukaryotes, these channels are known to exhibit a unique gating mechanism, which appears to be triggered by the permeant Cl− anion. We infer details of this gating mechanism by studying the free energetics of Cl− occupancy in the pore of a prokaryotic ClC homolog. These free energetics were gleaned from 30 ns of molecular dynamics simulation on an ∼133,000-atom system consisting of a hydrated membrane embedded StClC transporter. The binding sites for Cl− in the transporter were determined for the cases where the putative gating residue, Glu148, was protonated and unprotonated. When the glutamate gate is protonated, Cl− favorably occupies an exterior site, Sext, to form a queue of anions in the pore. However, when the glutamate gate is unprotonated, Cl− cannot occupy this site nor, consequently, pass through the pore. An additional, previously undetected, site was found in the pore near the outer membrane that exists regardless of the protonation state of Glu148. Although this suggests that, for the prokaryotic homolog, protonation of Glu148 may be the first step in transporting Cl− at the expense of H+ transport in the opposite direction, an evolutionary argument might suggest that Cl− opens the ClC gate in eukaryotic channels by inducing the conserved glutamate's protonation. During an additional 20 ns free dynamics simulation, the newly discovered outermost site, Sout, and the innermost site, Sint, were seen to allow spontaneous exchange of Cl− ions with the bulk electrolyte while under depolarization conditions. PMID:15345547

Inactivation gating of Kv7.1 channels does not involve concerted cooperative subunit interactions.

PubMed

Meisel, Eshcar; Tobelaim, William; Dvir, Meidan; Haitin, Yoni; Peretz, Asher; Attali, Bernard

2018-01-01

Inactivation is an intrinsic property of numerous voltage-gated K + (Kv) channels and can occur by N-type or/and C-type mechanisms. N-type inactivation is a fast, voltage independent process, coupled to activation, with each inactivation particle of a tetrameric channel acting independently. In N-type inactivation, a single inactivation particle is necessary and sufficient to occlude the pore. C-type inactivation is a slower process, involving the outermost region of the pore and is mediated by a concerted, highly cooperative interaction between all four subunits. Inactivation of Kv7.1 channels does not exhibit the hallmarks of N- and C-type inactivation. Inactivation of WT Kv7.1 channels can be revealed by hooked tail currents that reflects the recovery from a fast and voltage-independent inactivation process. However, several Kv7.1 mutants such as the pore mutant L273F generate an additional voltage-dependent slow inactivation. The subunit interactions during this slow inactivation gating remain unexplored. The goal of the present study was to study the nature of subunit interactions along Kv7.1 inactivation gating, using concatenated tetrameric Kv7.1 channel and introducing sequentially into each of the four subunits the slow inactivating pore mutation L273F. Incorporating an incremental number of inactivating mutant subunits did not affect the inactivation kinetics but slowed down the recovery kinetics from inactivation. Results indicate that Kv7.1 inactivation gating is not compatible with a concerted cooperative process. Instead, adding an inactivating subunit L273F into the Kv7.1 tetramer incrementally stabilizes the inactivated state, which suggests that like for activation gating, Kv7.1 slow inactivation gating is not a concerted process.

Coupled gating of skeletal muscle ryanodine receptors is modulated by Ca2+, Mg2+, and ATP

PubMed Central

Porta, Maura; Diaz-Sylvester, Paula L.; Neumann, Jake T.; Escobar, Ariel L.; Fleischer, Sidney

2012-01-01

Coupled gating (synchronous openings and closures) of groups of skeletal muscle ryanodine receptors (RyR1), which mimics RyR1-mediated Ca2+ release underlying Ca2+ sparks, was first described by Marx et al. (Marx SO, Ondrias K, Marks AR. Science 281: 818–821, 1998). The nature of the RyR1-RyR1 interactions for coupled gating still needs to be characterized. Consequently, we defined planar lipid bilayer conditions where ∼25% of multichannel reconstitutions contain mixtures of coupled and independently gating RyR1. In ∼10% of the cases, all RyRs (2–10 channels; most frequently 3–4) gated in coupled fashion, allowing for quantification. Our results indicated that coupling required cytosolic solutions containing ATP/Mg2+ and high (50 mM) luminal Ca2+ (Calum) or Sr2+ solutions. Bursts of coupled activity (events) started and ended abruptly, with all channels activating/deactivating within ∼300 μs. Coupled RyR1 were heterogeneous, where highly active RyR1 (“drivers”) seemed open during the entire coupled event (Po = 1), while other RyR1s (“followers”) displayed abundant flickering and smaller amplitude. Drivers mean open time increased with cytosolic Ca2+ (Cacyt) or caffeine, whereas followers flicker frequency was Cacyt independent and more sensitive to inhibition by cytosolic Mg2+. Coupled events were insensitive to varying lumen-to-cytosol Ca2+ fluxes from ∼1 to 8 pA, which does not corroborate coupling of neighboring RyR1 by local Ca2+-induced Ca2+ release. However, coupling requires specific Calum sites, as it was lost when Calum was replaced by luminal Ba2+ or Mg2+. In summary, coupled events reveal complex interactions among heterogeneous RyR1, differentially modulated by cytosolic ATP/Mg2+, Cacyt, and Calum, which under cell-like ionic conditions may parallel synchronous RyR1 gating during Ca2+ sparks. PMID:22785120

Estimating dynamic permeability in fractal pore network saturated by Maxwellian fluid

NASA Astrophysics Data System (ADS)

Sun, W.

2017-12-01

The frequency dependent flow of fluid in porous media is an important issue in geophysical prospecting. Oscillating flow in pipe leads to frequency dependent dynamic permeability and has been studied in pore network containing Newtonian fluid. But there is little work on oscillating complex fluid in pipe network, especially in irregular network. Here we formulated frequency dependent permeability for Maxwellian fluid and estimated the permeability in three-dimensional fractal network model. We consider an infinitely long cylindrical pipe with rigid solid wall. The pipe is filled with Maxwellian fluids. Based on the mass conservation equation, the equilibrium equation of force and Maxwell constitutive relationship, we formulated the flux by integration of axial velocity component over the pipe's cross section. Then we extend single pipe formulation to a 3D irregular network. Flux balance condition yields a set of linear equations whose unknowns are the fluid pressure at each node. By evaluating the total flow flux through the network, the dynamic permeability can be calculated.We investigated the dynamic permeability of brine and CPyCl/NaSal in a 3D porous sample with a cubic side length 1 cm. The pore network is created by a Voronoi cell filling method. The porosity, i.e., volume ratio between pore/pipe network and the overall cubic, is set as 0.1. The irregular pore network has a fractal structure. The dimension d of the pore network is defined by the relation between node number M within a sphere and the radius r of the sphere,M=rd.The results show that both brine and Maxwellian fluid's permeability maintain a stable value at low frequency, then decreases with fluctuating peaks. The dynamic permeability in pore networks saturated by Maxwellian fluid (CPyCl/NaSal (60 mM)) show larger peaks during the decline process at high frequency, which represents the typical resonance behavior. Dynamic permeability shows clear dependence on the dimension of the fractal

Qubit Architecture with High Coherence and Fast Tunable Coupling.

PubMed

Chen, Yu; Neill, C; Roushan, P; Leung, N; Fang, M; Barends, R; Kelly, J; Campbell, B; Chen, Z; Chiaro, B; Dunsworth, A; Jeffrey, E; Megrant, A; Mutus, J Y; O'Malley, P J J; Quintana, C M; Sank, D; Vainsencher, A; Wenner, J; White, T C; Geller, Michael R; Cleland, A N; Martinis, John M

2014-11-28

We introduce a superconducting qubit architecture that combines high-coherence qubits and tunable qubit-qubit coupling. With the ability to set the coupling to zero, we demonstrate that this architecture is protected from the frequency crowding problems that arise from fixed coupling. More importantly, the coupling can be tuned dynamically with nanosecond resolution, making this architecture a versatile platform with applications ranging from quantum logic gates to quantum simulation. We illustrate the advantages of dynamical coupling by implementing a novel adiabatic controlled-z gate, with a speed approaching that of single-qubit gates. Integrating coherence and scalable control, the introduced qubit architecture provides a promising path towards large-scale quantum computation and simulation.

Two-pore channels (TPCs): Novel voltage-gated ion channels with pleiotropic functions

PubMed Central

Feijóo-Bandín, Sandra; García-Vence, María; García-Rúa, Vanessa; Roselló-Lletí, Esther; Portolés, Manuel; Rivera, Miguel; González-Juanatey, José Ramón; Lago, Francisca

2017-01-01

ABSTRACT Two-pore channels (TPC1-3) comprise a subfamily of the eukaryotic voltage-gated ion channels (VGICs) superfamily that are mainly expressed in acidic stores in plants and animals. TPCS are widespread across the animal kingdom, with primates, mice and rats lacking TPC3, and mainly act as Ca+ and Na+ channels, although it was also suggested that they could be permeable to other ions. Nowadays, TPCs have been related to the development of different diseases, including Parkinson´s disease, obesity or myocardial ischemia. Due to this, their study has raised the interest of the scientific community to try to understand their mechanism of action in order to be able to develop an efficient drug that could regulate TPCs activity. In this review, we will provide an updated view regarding TPCs structure, function and activation, as well as their role in different pathophysiological processes. PMID:27440385

The Challenges to Coupling Dynamic Geospatial Models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goldstein, N

2006-06-23

Many applications of modeling spatial dynamic systems focus on a single system and a single process, ignoring the geographic and systemic context of the processes being modeled. A solution to this problem is the coupled modeling of spatial dynamic systems. Coupled modeling is challenging for both technical reasons, as well as conceptual reasons. This paper explores the benefits and challenges to coupling or linking spatial dynamic models, from loose coupling, where information transfer between models is done by hand, to tight coupling, where two (or more) models are merged as one. To illustrate the challenges, a coupled model of Urbanizationmore » and Wildfire Risk is presented. This model, called Vesta, was applied to the Santa Barbara, California region (using real geospatial data), where Urbanization and Wildfires occur and recur, respectively. The preliminary results of the model coupling illustrate that coupled modeling can lead to insight into the consequences of processes acting on their own.« less

Gating based on internal/external signals with dynamic correlation updates.

PubMed

Wu, Huanmei; Zhao, Qingya; Berbeco, Ross I; Nishioka, Seiko; Shirato, Hiroki; Jiang, Steve B

2008-12-21

Precise localization of mobile tumor positions in real time is critical to the success of gated radiotherapy. Tumor positions are usually derived from either internal or external surrogates. Fluoroscopic gating based on internal surrogates, such as implanted fiducial markers, is accurate however requiring a large amount of imaging dose. Gating based on external surrogates, such as patient abdominal surface motion, is non-invasive however less accurate due to the uncertainty in the correlation between tumor location and external surrogates. To address these complications, we propose to investigate an approach based on hybrid gating with dynamic internal/external correlation updates. In this approach, the external signal is acquired at high frequency (such as 30 Hz) while the internal signal is sparsely acquired (such as 0.5 Hz or less). The internal signal is used to validate and update the internal/external correlation during treatment. Tumor positions are derived from the external signal based on the newly updated correlation. Two dynamic correlation updating algorithms are introduced. One is based on the motion amplitude and the other is based on the motion phase. Nine patients with synchronized internal/external motion signals are simulated retrospectively to evaluate the effectiveness of hybrid gating. The influences of different clinical conditions on hybrid gating, such as the size of gating windows, the optimal timing for internal signal acquisition and the acquisition frequency are investigated. The results demonstrate that dynamically updating the internal/external correlation in or around the gating window will reduce false positive with relatively diminished treatment efficiency. This improvement will benefit patients with mobile tumors, especially greater for early stage lung cancers, for which the tumors are less attached or freely floating in the lung.

Effect of Pore Pressure on Slip Failure of an Impermeable Fault: A Coupled Micro Hydro-Geomechanical Model

NASA Astrophysics Data System (ADS)

Yang, Z.; Juanes, R.

2015-12-01

The geomechanical processes associated with subsurface fluid injection/extraction is of central importance for many industrial operations related to energy and water resources. However, the mechanisms controlling the stability and slip motion of a preexisting geologic fault remain poorly understood and are critical for the assessment of seismic risk. In this work, we develop a coupled hydro-geomechanical model to investigate the effect of fluid injection induced pressure perturbation on the slip behavior of a sealing fault. The model couples single-phase flow in the pores and mechanics of the solid phase. Granular packs (see example in Fig. 1a) are numerically generated where the grains can be either bonded or not, depending on the degree of cementation. A pore network is extracted for each granular pack with pore body volumes and pore throat conductivities calculated rigorously based on geometry of the local pore space. The pore fluid pressure is solved via an explicit scheme, taking into account the effect of deformation of the solid matrix. The mechanics part of the model is solved using the discrete element method (DEM). We first test the validity of the model with regard to the classical one-dimensional consolidation problem where an analytical solution exists. We then demonstrate the ability of the coupled model to reproduce rock deformation behavior measured in triaxial laboratory tests under the influence of pore pressure. We proceed to study the fault stability in presence of a pressure discontinuity across the impermeable fault which is implemented as a plane with its intersected pore throats being deactivated and thus obstructing fluid flow (Fig. 1b, c). We focus on the onset of shear failure along preexisting faults. We discuss the fault stability criterion in light of the numerical results obtained from the DEM simulations coupled with pore fluid flow. The implication on how should faults be treated in a large-scale continuum model is also presented.

Adsorption-Coupled Diffusion of Gold Nanoclusters within a Large-Pore Protein Crystal Scaffold.

PubMed

Hartje, Luke F; Munsky, Brian; Ni, Thomas W; Ackerson, Christopher J; Snow, Christopher D

2017-08-17

Large-pore protein crystals (LPCs) are ordered biologically derived nanoporous materials exhibiting pore diameters greater than 8 nm. These substantial pores distinguish LPCs from typical nanoporous scaffolds, enabling engineered LPC materials to readily uptake, immobilize, and release macromolecular guests. In this study, macromolecular transport within an LPC environment was experimentally and computationally investigated by studying adsorption-coupled diffusion of Au 25 (glutathione) 18 nanoclusters within a cross-linked LPC scaffold via time-lapse confocal microscopy, bulk equilibrium adsorption, and hindered diffusion simulation. Equilibrium adsorption data is congruent with a Langmuir adsorption model, exhibiting strong binding behavior between nanoclusters and the scaffold. The standard Gibbs free energy of binding is equivalent to -37.2 kJ/mol, and the maximum binding capacity of 1.25 × 10 3 mg/g corresponds to approximately 29 nanoclusters per LPC unit cell. The hindered diffusion model showed good agreement with experimental data, revealing a pore diffusion coefficient of 3.7 × 10 -7 cm 2 /s under low nanocluster concentration. Furthermore, the model was sufficient to determine adsorption and desorption kinetic values for k a and k d equal to 13 cm 3 /mol·s and 1.7 × 10 -7 s -1 , respectively. At higher nanocluster concentrations, the simulated pore diffusion coefficient could be reduced by 3 orders of magnitude to 3.4 × 10 -10 cm 2 /s due to the effects of pore occlusion. This study demonstrates a strategy to analyze adsorption-coupled diffusion data to better understand complex transport of fluorescent macromolecules into LPCs. This approach fits the observable fluorescence data to the key molecular details and will benefit downstream efforts to engineer LPC-based nanoporous materials.

mTor Regulates Lysosomal ATP-sensitive Two-Pore Na+ Channel to Adapt to Metabolic State

PubMed Central

Navarro, Betsy; Seo, Young-jun; Aranda, Kimberly; Shi, Lucy; Battaglia-Hsu, Shyuefang; Nissim, Itzhak; Clapham, David E.; Ren, Dejian

2014-01-01

SUMMARY Survival in the wild requires organismal adaptations to the availability of nutrients. Endosomes and lysosomes are key intracellular organelles that couple nutrition and metabolic status to cellular responses, but how they detect cytosolic ATP levels is not well understood. Here we identify an endolysosomal ATP-sensitive Na+ channel (lysoNaATP). The channel is a complex formed by Two-Pore Channels (TPC1 and TPC2), ion channels previously thought to be gated by nicotinic acid adenine dinucleotide phosphate (NAADP), and the mammalian target of rapamycin (mTOR). The channel complex detects nutrient status, becomes constitutively open upon nutrient removal and mTOR translocation off the lysosomal membrane, and controls the lysosome's membrane potential, pH stability, and the amino acid homeostasis. Mutant mice lacking lysoNaATP have much reduced exercise endurance after fasting. Thus, TPCs are a new ion channel family that couple the cell's metabolic state to endolysosomal function and are crucial for physical endurance during food restriction. PMID:23394946

Voltage-sensing domain mode shift is coupled to the activation gate by the N-terminal tail of hERG channels.

PubMed

Tan, Peter S; Perry, Matthew D; Ng, Chai Ann; Vandenberg, Jamie I; Hill, Adam P

2012-09-01

Human ether-a-go-go-related gene (hERG) potassium channels exhibit unique gating kinetics characterized by unusually slow activation and deactivation. The N terminus of the channel, which contains an amphipathic helix and an unstructured tail, has been shown to be involved in regulation of this slow deactivation. However, the mechanism of how this occurs and the connection between voltage-sensing domain (VSD) return and closing of the gate are unclear. To examine this relationship, we have used voltage-clamp fluorometry to simultaneously measure VSD motion and gate closure in N-terminally truncated constructs. We report that mode shifting of the hERG VSD results in a corresponding shift in the voltage-dependent equilibrium of channel closing and that at negative potentials, coupling of the mode-shifted VSD to the gate defines the rate of channel closure. Deletion of the first 25 aa from the N terminus of hERG does not alter mode shifting of the VSD but uncouples the shift from closure of the cytoplasmic gate. Based on these observations, we propose the N-terminal tail as an adaptor that couples voltage sensor return to gate closure to define slow deactivation gating in hERG channels. Furthermore, because the mode shift occurs on a time scale relevant to the cardiac action potential, we suggest a physiological role for this phenomenon in maximizing current flow through hERG channels during repolarization.

The HOOK region of voltage-gated Ca2+ channel β subunits senses and transmits PIP2 signals to the gate.

PubMed

Park, Cheon-Gyu; Park, Yongsoo; Suh, Byung-Chang

2017-02-01

The β subunit of voltage-gated Ca 2+ (Ca V ) channels plays an important role in regulating gating of the α1 pore-forming subunit and its regulation by phosphatidylinositol 4,5-bisphosphate (PIP 2 ). Subcellular localization of the Ca V β subunit is critical for this effect; N-terminal-dependent membrane targeting of the β subunit slows inactivation and decreases PIP 2 sensitivity. Here, we provide evidence that the HOOK region of the β subunit plays an important role in the regulation of Ca V biophysics. Based on amino acid composition, we broadly divide the HOOK region into three domains: S (polyserine), A (polyacidic), and B (polybasic). We show that a β subunit containing only its A domain in the HOOK region increases inactivation kinetics and channel inhibition by PIP 2 depletion, whereas a β subunit with only a B domain decreases these responses. When both the A and B domains are deleted, or when the entire HOOK region is deleted, the responses are elevated. Using a peptide-to-liposome binding assay and confocal microscopy, we find that the B domain of the HOOK region directly interacts with anionic phospholipids via polybasic and two hydrophobic Phe residues. The β2c-short subunit, which lacks an A domain and contains fewer basic amino acids and no Phe residues in the B domain, neither associates with phospholipids nor affects channel gating dynamically. Together, our data suggest that the flexible HOOK region of the β subunit acts as an important regulator of Ca V channel gating via dynamic electrostatic and hydrophobic interaction with the plasma membrane. © 2017 Park et al.

Position-Dependent Dynamics Explain Pore-Averaged Diffusion in Strongly Attractive Adsorptive Systems.

PubMed

Krekelberg, William P; Siderius, Daniel W; Shen, Vincent K; Truskett, Thomas M; Errington, Jeffrey R

2017-12-12

Using molecular simulations, we investigate the relationship between the pore-averaged and position-dependent self-diffusivity of a fluid adsorbed in a strongly attractive pore as a function of loading. Previous work (Krekelberg, W. P.; Siderius, D. W.; Shen, V. K.; Truskett, T. M.; Errington, J. R. Connection between thermodynamics and dynamics of simple fluids in highly attractive pores. Langmuir 2013, 29, 14527-14535, doi: 10.1021/la4037327) established that pore-averaged self-diffusivity in the multilayer adsorption regime, where the fluid exhibits a dense film at the pore surface and a lower density interior pore region, is nearly constant as a function of loading. Here we show that this puzzling behavior can be understood in terms of how loading affects the fraction of particles that reside in the film and interior pore regions as well as their distinct dynamics. Specifically, the insensitivity of pore-averaged diffusivity to loading arises from the approximate cancellation of two factors: an increase in the fraction of particles in the higher diffusivity interior pore region with loading and a corresponding decrease in the particle diffusivity in that region. We also find that the position-dependent self-diffusivities scale with the position-dependent density. We present a model for predicting the pore-average self-diffusivity based on the position-dependent self-diffusivity, which captures the unusual characteristics of pore-averaged self-diffusivity in strongly attractive pores over several orders of magnitude.

A Finite Element Framework for Studying the Mechanical Response of Macromolecules: Application to the Gating of the Mechanosensitive Channel MscL

PubMed Central

Tang, Yuye; Cao, Guoxin; Chen, Xi; Yoo, Jejoong; Yethiraj, Arun; Cui, Qiang

2006-01-01

The gating pathways of mechanosensitive channels of large conductance (MscL) in two bacteria (Mycobacterium tuberculosis and Escherichia coli) are studied using the finite element method. The phenomenological model treats transmembrane helices as elastic rods and the lipid membrane as an elastic sheet of finite thickness; the model is inspired by the crystal structure of MscL. The interactions between various continuum components are derived from molecular-mechanics energy calculations using the CHARMM all-atom force field. Both bacterial MscLs open fully upon in-plane tension in the membrane and the variation of pore diameter with membrane tension is found to be essentially linear. The estimated gating tension is close to the experimental value. The structural variations along the gating pathway are consistent with previous analyses based on structural models with experimental constraints and biased atomistic molecular-dynamics simulations. Upon membrane bending, neither MscL opens substantially, although there is notable and nonmonotonic variation in the pore radius. This emphasizes that the gating behavior of MscL depends critically on the form of the mechanical perturbation and reinforces the idea that the crucial gating parameter is lateral tension in the membrane rather than the curvature of the membrane. Compared to popular all-atom-based techniques such as targeted or steered molecular-dynamics simulations, the finite element method-based continuum-mechanics framework offers a unique alternative to bridge detailed intermolecular interactions and biological processes occurring at large spatial scales and long timescales. It is envisioned that such a hierarchical multiscale framework will find great value in the study of a variety of biological processes involving complex mechanical deformations such as muscle contraction and mechanotransduction. PMID:16731564

Multi-qubit gates protected by adiabaticity and dynamical decoupling applicable to donor qubits in silicon

DOE PAGES

Witzel, Wayne; Montano, Ines; Muller, Richard P.; ...

2015-08-19

In this paper, we present a strategy for producing multiqubit gates that promise high fidelity with minimal tuning requirements. Our strategy combines gap protection from the adiabatic theorem with dynamical decoupling in a complementary manner. Energy-level transition errors are protected by adiabaticity and remaining phase errors are mitigated via dynamical decoupling. This is a powerful way to divide and conquer the various error channels. In order to accomplish this without violating a no-go theorem regarding black-box dynamically corrected gates [Phys. Rev. A 80, 032314 (2009)], we require a robust operating point (sweet spot) in control space where the qubits interactmore » with little sensitivity to noise. There are also energy gap requirements for effective adiabaticity. We apply our strategy to an architecture in Si with P donors where we assume we can shuttle electrons between different donors. Electron spins act as mobile ancillary qubits and P nuclear spins act as long-lived data qubits. Furthermore, this system can have a very robust operating point where the electron spin is bound to a donor in the quadratic Stark shift regime. High fidelity single qubit gates may be performed using well-established global magnetic resonance pulse sequences. Single electron-spin preparation and measurement has also been demonstrated. Thus, putting this all together, we present a robust universal gate set for quantum computation.« less

Influence of the Location of Attractive Polymer-Pore Interactions on Translocation Dynamics.

PubMed

Ghosh, Bappa; Chaudhury, Srabanti

2018-01-11

We probe the influence of polymer-pore interactions on the translocation dynamics using Langevin dynamics simulations. We investigate the effect of the strength and location of the polymer-pore interaction using nanopores that are partially charged either at the entry or the exit or on both sides of the pore. We study the change in the translocation time as a function of the strength of the polymer-pore interaction for a given chain length and under the effect of an externally applied field. Under a moderate driving force and a chain length longer than the length of the pore, the translocation time shows a nonmonotonic increase with an increase in the attractive interaction. Also, an interaction on the cis side of the pore can increase the translocation probability. In the presence of an external field and a strong attractive force, the translocation time for shorter chains is independent of the polymer-pore interaction at the entry side of the pore, whereas an interaction on the trans side dominates the translocation process. Our simulation results are rationalized by a qualitative analysis of the free energy landscape for polymer translocation.

Outward Rectification of Voltage-Gated K+ Channels Evolved at Least Twice in Life History.

PubMed

Riedelsberger, Janin; Dreyer, Ingo; Gonzalez, Wendy

2015-01-01

Voltage-gated potassium (K+) channels are present in all living systems. Despite high structural similarities in the transmembrane domains (TMD), this K+ channel type segregates into at least two main functional categories-hyperpolarization-activated, inward-rectifying (Kin) and depolarization-activated, outward-rectifying (Kout) channels. Voltage-gated K+ channels sense the membrane voltage via a voltage-sensing domain that is connected to the conduction pathway of the channel. It has been shown that the voltage-sensing mechanism is the same in Kin and Kout channels, but its performance results in opposite pore conformations. It is not known how the different coupling of voltage-sensor and pore is implemented. Here, we studied sequence and structural data of voltage-gated K+ channels from animals and plants with emphasis on the property of opposite rectification. We identified structural hotspots that alone allow already the distinction between Kin and Kout channels. Among them is a loop between TMD S5 and the pore that is very short in animal Kout, longer in plant and animal Kin and the longest in plant Kout channels. In combination with further structural and phylogenetic analyses this finding suggests that outward-rectification evolved twice and independently in the animal and plant kingdom.

Outward Rectification of Voltage-Gated K+ Channels Evolved at Least Twice in Life History

PubMed Central

Riedelsberger, Janin; Dreyer, Ingo; Gonzalez, Wendy

2015-01-01

Voltage-gated potassium (K+) channels are present in all living systems. Despite high structural similarities in the transmembrane domains (TMD), this K+ channel type segregates into at least two main functional categories—hyperpolarization-activated, inward-rectifying (Kin) and depolarization-activated, outward-rectifying (Kout) channels. Voltage-gated K+ channels sense the membrane voltage via a voltage-sensing domain that is connected to the conduction pathway of the channel. It has been shown that the voltage-sensing mechanism is the same in Kin and Kout channels, but its performance results in opposite pore conformations. It is not known how the different coupling of voltage-sensor and pore is implemented. Here, we studied sequence and structural data of voltage-gated K+ channels from animals and plants with emphasis on the property of opposite rectification. We identified structural hotspots that alone allow already the distinction between Kin and Kout channels. Among them is a loop between TMD S5 and the pore that is very short in animal Kout, longer in plant and animal Kin and the longest in plant Kout channels. In combination with further structural and phylogenetic analyses this finding suggests that outward-rectification evolved twice and independently in the animal and plant kingdom. PMID:26356684

Secondary water pore formation for proton transport in a ClC exchanger revealed by an atomistic molecular-dynamics simulation.

PubMed

Ko, Youn Jo; Jo, Won Ho

2010-05-19

Several prokaryotic ClC proteins have been demonstrated to function as exchangers that transport both chloride ions and protons simultaneously in opposite directions. However, the path of the proton through the ClC exchanger, and how the protein brings about the coupled movement of both ions are still unknown. In this work, we use an atomistic molecular dynamics (MD) simulation to demonstrate that a previously unknown secondary water pore is formed inside an Escherichia coli ClC exchanger. The secondary water pore is bifurcated from the chloride ion pathway at E148. From the systematic simulations, we determined that the glutamate residue exposed to the intracellular solution, E203, plays an important role as a trigger for the formation of the secondary water pore, and that the highly conserved tyrosine residue Y445 functions as a barrier that separates the proton from the chloride ion pathways. Based on our simulation results, we conclude that protons in the ClC exchanger are conducted via a water network through the secondary water pore, and we propose a new mechanism for the coupled transport of chloride ions and protons. It has been reported that several members of ClC proteins are not just channels that simply transport chloride ions across lipid bilayers; rather, they are exchangers that transport both the chloride ion and proton in opposite directions. However, the ion transit pathways and the mechanism of the coupled movement of these two ions have not yet been unveiled. In this article, we report a new finding (to our knowledge) of a water pore inside a prokaryotic ClC protein as revealed by computer simulation. This water pore is bifurcated from the putative chloride ion, and water molecules inside the new pore connect two glutamate residues that are known to be key residues for proton transport. On the basis of our simulation results, we conclude that the water wire that is formed inside the newly found pore acts as a proton pathway, which enables us to

Heralded quantum controlled-phase gates with dissipative dynamics in macroscopically distant resonators

NASA Astrophysics Data System (ADS)

Qin, Wei; Wang, Xin; Miranowicz, Adam; Zhong, Zhirong; Nori, Franco

2017-07-01

Heralded near-deterministic multiqubit controlled-phase gates with integrated error detection have recently been proposed by Borregaard et al. [Phys. Rev. Lett. 114, 110502 (2015), 10.1103/PhysRevLett.114.110502]. This protocol is based on a single four-level atom (a heralding quartit) and N three-level atoms (operational qutrits) coupled to a single-resonator mode acting as a cavity bus. Here we generalize this method for two distant resonators without the cavity bus between the heralding and operational atoms. Specifically, we analyze the two-qubit controlled-Z gate and its multiqubit-controlled generalization (i.e., a Toffoli-like gate) acting on the two-lowest levels of N qutrits inside one resonator, with their successful actions being heralded by an auxiliary microwave-driven quartit inside the other resonator. Moreover, we propose a circuit-quantum-electrodynamics realization of the protocol with flux and phase qudits in linearly coupled transmission-line resonators with dissipation. These methods offer a quadratic fidelity improvement compared to cavity-assisted deterministic gates.

Hydrophobic interactions between the voltage sensor and pore mediate inactivation in Kv11.1 channels

PubMed Central

Perry, Matthew D.; Wong, Sophia; Ng, Chai Ann

2013-01-01

Kv11.1 channels are critical for the maintenance of a normal heart rhythm. The flow of potassium ions through these channels is controlled by two voltage-regulated gates, termed “activation” and “inactivation,” located at opposite ends of the pore. Crucially in Kv11.1 channels, inactivation gating occurs much more rapidly, and over a distinct range of voltages, compared with activation gating. Although it is clear that the fourth transmembrane segments (S4), within each subunit of the tetrameric channel, are important for controlling the opening and closing of the activation gate, their role during inactivation gating is much less clear. Here, we use rate equilibrium free energy relationship (REFER) analysis to probe the contribution of the S4 “voltage-sensor” helix during inactivation of Kv11.1 channels. Contrary to the important role that charged residues play during activation gating, it is the hydrophobic residues (Leu529, Leu530, Leu532, and Val535) that are the key molecular determinants of inactivation gating. Within the context of an interconnected multi-domain model of Kv11.1 inactivation gating, our REFER analysis indicates that the S4 helix and the S4–S5 linker undergo a conformational rearrangement shortly after that of the S5 helix and S5P linker, but before the S6 helix. Combining REFER analysis with double mutant cycle analysis, we provide evidence for a hydrophobic interaction between residues on the S4 and S5 helices. Based on a Kv11.1 channel homology model, we propose that this hydrophobic interaction forms the basis of an intersubunit coupling between the voltage sensor and pore domain that is an important mediator of inactivation gating. PMID:23980196

Unfolding of a temperature-sensitive domain controls voltage-gated channel activation

PubMed Central

Arrigoni, Cristina; Rohaim, Ahmed; Shaya, David; Findeisen, Felix; Stein, Richard A.; Nurva, Shailika Reddy; Mishra, Smriti; Mchaourab, Hassane S.; Minor, Daniel L.

2016-01-01

Voltage-gated ion channels (VGICs) are outfitted with diverse cytoplasmic domains that impact function. To examine how such elements may affect VGIC behavior, we addressed how the bacterial voltage-gated sodium channel (BacNaV) C-terminal cytoplasmic domain (CTD) affects function. Our studies show that the BacNaV CTD exerts a profound influence on gating through a temperature-dependent unfolding transition in a discrete cytoplasmic domain, the neck domain, proximal to the pore. Structural and functional studies establish that the BacNaV CTD comprises a bi-partite four-helix bundle that bears an unusual hydrophilic core whose integrity is central to the unfolding mechanism and that couples directly to the channel activation gate. Together, our findings define a general principle for how the widespread four-helix bundle cytoplasmic domain architecture can control VGIC responses, uncover a mechanism underlying the diverse BacNaV voltage dependencies, and demonstrate that a discrete domain can encode the temperature dependent response of a channel. PMID:26919429

Two-qubit gates and coupling with low-impedance flux qubits

NASA Astrophysics Data System (ADS)

Chow, Jerry; Corcoles, Antonio; Rigetti, Chad; Rozen, Jim; Keefe, George; Rothwell, Mary-Beth; Rohrs, John; Borstelmann, Mark; Divincenzo, David; Ketchen, Mark; Steffen, Matthias

2011-03-01

We experimentally demonstrate the coupling of two low-impedance flux qubits mediated via a transmission line resonator. We explore the viability of experimental coupling protocols which involve selective microwave driving on the qubits independently as well as fast frequency tuning through on-chip flux-bias. Pulse-shaping techniques for single-qubit and two-qubit gates are employed for reducing unwanted leakage and phase errors. A joint readout through the transmission line resonator is used for characterizing single-qubit and two-qubit states.

Dynamin-related protein-1 controls fusion pore dynamics during platelet granule exocytosis.

PubMed

Koseoglu, Secil; Dilks, James R; Peters, Christian G; Fitch-Tewfik, Jennifer L; Fadel, Nathalie A; Jasuja, Reema; Italiano, Joseph E; Haynes, Christy L; Flaumenhaft, Robert

2013-03-01

Platelet granule exocytosis serves a central role in hemostasis and thrombosis. Recently, single-cell amperometry has shown that platelet membrane fusion during granule exocytosis results in the formation of a fusion pore that subsequently expands to enable the extrusion of granule contents. However, the molecular mechanisms that control platelet fusion pore expansion and collapse are not known. We identified dynamin-related protein-1 (Drp1) in platelets and found that an inhibitor of Drp1, mdivi-1, blocked exocytosis of both platelet dense and α-granules. We used single-cell amperometry to monitor serotonin release from individual dense granules and, thereby, measured the effect of Drp1 inhibition on fusion pore dynamics. Inhibition of Drp1 increased spike width and decreased prespike foot events, indicating that Drp1 influences fusion pore formation and expansion. Platelet-mediated thrombus formation in vivo after laser-induced injury of mouse cremaster arterioles was impaired after infusion of mdivi-1. These results demonstrate that inhibition of Drp1 disrupts platelet fusion pore dynamics and indicate that Drp1 can be targeted to control thrombus formation in vivo.

Advanced insulated gate bipolar transistor gate drive

DOEpatents

Short, James Evans [Monongahela, PA; West, Shawn Michael [West Mifflin, PA; Fabean, Robert J [Donora, PA

2009-08-04

A gate drive for an insulated gate bipolar transistor (IGBT) includes a control and protection module coupled to a collector terminal of the IGBT, an optical communications module coupled to the control and protection module, a power supply module coupled to the control and protection module and an output power stage module with inputs coupled to the power supply module and the control and protection module, and outputs coupled to a gate terminal and an emitter terminal of the IGBT. The optical communications module is configured to send control signals to the control and protection module. The power supply module is configured to distribute inputted power to the control and protection module. The control and protection module outputs on/off, soft turn-off and/or soft turn-on signals to the output power stage module, which, in turn, supplies a current based on the signal(s) from the control and protection module for charging or discharging an input capacitance of the IGBT.

Two-pore channels at the intersection of endolysosomal membrane traffic

PubMed Central

Marchant, Jonathan S.; Patel, Sandip

2016-01-01

Two-pore channels (TPCs) are ancient members of the voltage-gated ion channel superfamily that localize to acidic organelles such as lysosomes. The TPC complex is the proposed target of the Ca2 +-mobilizing messenger NAADP, which releases Ca2 + from these acidic Ca2 + stores. Whereas details of TPC activation and native ion permeation remain unclear, a consensus has emerged around their function in regulating endolysosomal trafficking. This role is supported by recent proteomic data showing that TPCs interact with proteins controlling membrane organization and dynamics, including Rab GTPases and components of the fusion apparatus. Regulation of TPCs by PtdIns(3,5)P2 and/or NAADP (nicotinic acid adenine dinucleotide phosphate) together with their functional and physical association with Rab proteins provides a mechanism for coupling phosphoinositide and trafficking protein cues to local ion fluxes. Therefore, TPCs work at the regulatory cross-roads of (patho)physiological cues to co-ordinate and potentially deregulate traffic flow through the endolysosomal network. This review focuses on the native role of TPCs in trafficking and their emerging contributions to endolysosomal trafficking dysfunction. PMID:26009187

Toward prethreshold gate-based quantum simulation of chemical dynamics: using potential energy surfaces to simulate few-channel molecular collisions

DOE PAGES

Sornborger, Andrew Tyler; Stancil, Phillip; Geller, Michael R.

2018-03-22

Here, one of the most promising applications of an error-corrected universal quantum computer is the efficient simulation of complex quantum systems such as large molecular systems. In this application, one is interested in both the electronic structure such as the ground state energy and dynamical properties such as the scattering cross section and chemical reaction rates. However, most theoretical work and experimental demonstrations have focused on the quantum computation of energies and energy surfaces. In this work, we attempt to make the prethreshold (not error-corrected) quantum simulation of dynamical properties practical as well. We show that the use of precomputedmore » potential energy surfaces and couplings enables the gate-based simulation of few-channel but otherwise realistic molecular collisions. Our approach is based on the widely used Born–Oppenheimer approximation for the structure problem coupled with a semiclassical method for the dynamics. In the latter the electrons are treated quantum mechanically but the nuclei are classical, which restricts the collisions to high energy or temperature (typically above ≈10 eV). By using operator splitting techniques optimized for the resulting time-dependent Hamiltonian simulation problem, we give several physically realistic collision examples, with 3–8 channels and circuit depths < 1000.« less

Toward prethreshold gate-based quantum simulation of chemical dynamics: using potential energy surfaces to simulate few-channel molecular collisions

NASA Astrophysics Data System (ADS)

Sornborger, Andrew T.; Stancil, Phillip; Geller, Michael R.

2018-05-01

One of the most promising applications of an error-corrected universal quantum computer is the efficient simulation of complex quantum systems such as large molecular systems. In this application, one is interested in both the electronic structure such as the ground state energy and dynamical properties such as the scattering cross section and chemical reaction rates. However, most theoretical work and experimental demonstrations have focused on the quantum computation of energies and energy surfaces. In this work, we attempt to make the prethreshold (not error-corrected) quantum simulation of dynamical properties practical as well. We show that the use of precomputed potential energy surfaces and couplings enables the gate-based simulation of few-channel but otherwise realistic molecular collisions. Our approach is based on the widely used Born-Oppenheimer approximation for the structure problem coupled with a semiclassical method for the dynamics. In the latter the electrons are treated quantum mechanically but the nuclei are classical, which restricts the collisions to high energy or temperature (typically above ≈ 10 eV). By using operator splitting techniques optimized for the resulting time-dependent Hamiltonian simulation problem, we give several physically realistic collision examples, with 3-8 channels and circuit depths < 1000.

Toward prethreshold gate-based quantum simulation of chemical dynamics: using potential energy surfaces to simulate few-channel molecular collisions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sornborger, Andrew Tyler; Stancil, Phillip; Geller, Michael R.

Here, one of the most promising applications of an error-corrected universal quantum computer is the efficient simulation of complex quantum systems such as large molecular systems. In this application, one is interested in both the electronic structure such as the ground state energy and dynamical properties such as the scattering cross section and chemical reaction rates. However, most theoretical work and experimental demonstrations have focused on the quantum computation of energies and energy surfaces. In this work, we attempt to make the prethreshold (not error-corrected) quantum simulation of dynamical properties practical as well. We show that the use of precomputedmore » potential energy surfaces and couplings enables the gate-based simulation of few-channel but otherwise realistic molecular collisions. Our approach is based on the widely used Born–Oppenheimer approximation for the structure problem coupled with a semiclassical method for the dynamics. In the latter the electrons are treated quantum mechanically but the nuclei are classical, which restricts the collisions to high energy or temperature (typically above ≈10 eV). By using operator splitting techniques optimized for the resulting time-dependent Hamiltonian simulation problem, we give several physically realistic collision examples, with 3–8 channels and circuit depths < 1000.« less

Coupled Electro-Hydrodynamic Effects of Electro-Osmosis from Pore Scale to Darcy Scale

NASA Astrophysics Data System (ADS)

Schotting, R.; Joekar-Niasar, V.; Leijnse, A.

2011-12-01

Electro-osmosis is "movement of a fluid under the effect of an electric field in a porous medium". This phenomenon has many applications in civil engineering (slope stabilization, dewatering), environmental engineering (soil remediation, sludge dewatering), chemical engineering (micro- or nano- mixers), medical engineering (drug delivery), etc. The key factor in electro-osmosis is the competition between the electrochemical and hydrodynamic forces as well as the coupling between the solid surface and the electrolyte properties. The objective of this research is to understand the influence of pore-scale heterogeneities of surface properties on the Darcy-scale behavior. We develop novel analytical solutions for the flow and transport of electrolyte including electro-hydrodynamic forces in a single micro-channel. We propose the complete analytical solution for monovalent electrolyte at full range overlapping double layers, and nonlinear electric field, including the Donan effect in transport of ions. These pore-scale formulations are numerically upscaled to obtain the Darcy-scale behavior. Our results show the contribution of electro-osmotic, chemical-osmotic and hydrodynamic components of the flow equation on pressure field evolution and multi-directional flow field at Darcy scale.

Experimentally simulating the dynamics of quantum light and matter at ultrastrong coupling using circuit QED (1) - implementation and matter dynamics -

NASA Astrophysics Data System (ADS)

Kounalakis, M.; Langford, N. K.; Sagastizabal, R.; Dickel, C.; Bruno, A.; Luthi, F.; Thoen, D. J.; Endo, A.; Dicarlo, L.

The field dipole coupling of quantum light and matter, described by the quantum Rabi model, leads to exotic phenomena when the coupling strength g becomes comparable or larger than the atom and photon frequencies ωq , r. In this ultra-strong coupling regime, excitations are not conserved, leading to collapse-revival dynamics in atom and photon parity and Schrödinger-cat-like atom-photon entanglement. We realize a quantum simulation of the Rabi model using a transmon qubit coupled to a resonator. In this first part, we describe our analog-digital approach to implement up to 90 symmetric Trotter steps, combining single-qubit gates with the Jaynes-Cummings interaction naturally present in our circuit QED system. Controlling the phase of microwave pulses defines a rotating frame and enables simulation of arbitrary parameter regimes of the Rabi model. We demonstrate measurements of qubit parity dynamics showing revivals at g /ωr > 0 . 8 for ωq = 0 and characteristic dynamics for nondegenerate ωq from g / 4 to g. Funding from the EU FP7 Project ScaleQIT, an ERC Grant, the Dutch Research Organization NWO, and Microsoft Research.

Large scale rearrangement of protein domains is associated with voltage gating of the VDAC channel.

PubMed Central

Peng, S; Blachly-Dyson, E; Forte, M; Colombini, M

1992-01-01

The VDAC channel of the mitochondrial outer membrane is voltage-gated like the larger, more complex voltage-gated channels of the plasma membrane. However, VDAC is a low molecular weight (30 kDa), abundant protein, which is readily purified and reconstituted, making it an ideal system for analyzing the molecular basis for ion selectivity and voltage-gating. We have probed the VDAC channel by subjecting the cloned yeast (S. cerevisiae) VDAC gene to site-directed mutagenesis and introducing the resulting mutant channels into planar bilayers to detect the effects of specific sequence changes on channel properties. This approach has allowed us to formulate and test a model of the open state structure of the VDAC channel. Now we have applied the same approach to analyzing the structure of the channel's low-conducting "closed state" (essentially closed to important metabolites). We have identified protein domains forming the wall of the closed conformation and domains that seem to be removed from the wall of the pore during channel closure. The latter can explain the reduction in pore diameter and volume and the dramatically altered channel selectivity resulting from the channel closure. This process would make a natural coupling between motion of the sensor and channel gating. PMID:1376163

Fast optical cooling of a nanomechanical cantilever by a dynamical Stark-shift gate.

PubMed

Yan, Leilei; Zhang, Jian-Qi; Zhang, Shuo; Feng, Mang

2015-10-12

The efficient cooling of nanomechanical resonators is essential to exploration of quantum properties of the macroscopic or mesoscopic systems. We propose such a laser-cooling scheme for a nanomechanical cantilever, which works even for the low-frequency mechanical mode and under weak cooling lasers. The cantilever is coupled by a diamond nitrogen-vacancy center under a strong magnetic field gradient and the cooling is assisted by a dynamical Stark-shift gate. Our scheme can effectively enhance the desired cooling efficiency by avoiding the off-resonant and undesired carrier transitions, and thereby cool the cantilever down to the vicinity of the vibrational ground state in a fast fashion.

Fast optical cooling of a nanomechanical cantilever by a dynamical Stark-shift gate

PubMed Central

Yan, Leilei; Zhang, Jian-Qi; Zhang, Shuo; Feng, Mang

2015-01-01

The efficient cooling of nanomechanical resonators is essential to exploration of quantum properties of the macroscopic or mesoscopic systems. We propose such a laser-cooling scheme for a nanomechanical cantilever, which works even for the low-frequency mechanical mode and under weak cooling lasers. The cantilever is coupled by a diamond nitrogen-vacancy center under a strong magnetic field gradient and the cooling is assisted by a dynamical Stark-shift gate. Our scheme can effectively enhance the desired cooling efficiency by avoiding the off-resonant and undesired carrier transitions, and thereby cool the cantilever down to the vicinity of the vibrational ground state in a fast fashion. PMID:26455901

Pore-scale dynamics of salt transport in drying porous media

NASA Astrophysics Data System (ADS)

Shokri, N.

2013-12-01

Understanding the physics of water evaporation from saline porous media is important in many hydrological processes such as land-atmosphere interactions, water management, vegetation, soil salinity, and mineral-fluid interactions. We applied synchrotron x-ray micro-tomography to investigate the pore-scale dynamics of dissolved salt distribution in a three dimensional drying saline porous media using a cylindrical plastic column (15 mm in height and 8 mm in diameter) packed with sand particles saturated with CaI2 solution (5% concentration by mass) with a spatial and temporal resolution of 12 microns and 30 min, respectively. Every time the drying sand column was set to be imaged, two different images were recorded using distinct synchrotron X-rays energies immediately above (33.2690 keV) and below (33.0690 keV) the K-edge value of Iodine (33.1694 keV). Taking the difference between pixel gray values enabled us to delineate the spatial and temporal distribution of CaI2 concentration at pore scale. The experiment was continued for 12 hours. Results indicate that during early stages of evaporation, air preferentially invades large pores at the surface while finer pores remain saturated and connected to the wet zone at bottom via capillary-induced liquid flow. Consequently, the salt concentration increases preferentially in finer pores where evaporation occurs. The Peclet number (describing the competition between convection and diffusion) was greater than one in our experiment resulting in higher salt concentrations closer to the evaporation surface indicating a convection-driven process. The obtained salt profiles were used to evaluate the numerical solution of the convection-diffusion equation (CDE). Results show that the macro-scale CDE could capture the overall trend of the measured salt profiles but fail to produce the exact slope of the profiles. Our results shed new insight on the physics of salt transport and its complex dynamics in drying porous media and

Relating soil pore geometry to soil water content dynamics decomposed at multiple frequencies

NASA Astrophysics Data System (ADS)

Qin, Mingming; Gimenez, Daniel; Cooper, Miguel

2016-04-01

Soil structure is a critical factor determining the response of soil water content to meteorological inputs such as precipitation. Wavelet analysis can be used to filter a signal into several wavelet components, each characterizing a given frequency. The purpose of this research was to investigate relationships between the geometry of soil pore systems and the various wavelet components derived from soil water content dynamics. The two study sites investigated were located in the state of São Paulo, Brazil. Each site was comprised of five soil profiles, the first site was situated along a 300-meter transect with about 10% slope in a tropical semi-deciduous forest, while the second one spanned 230-meter over a Brazilian savanna with a slope of about 6%. For each profile, between two to four Water Content Reflectometer CS615 (Campbell Scientific, Inc.) probes were installed according to horizonation at depths varying between 0.1 m and 2.3 m. Bulk soil, three soil cores, and one undisturbed soil block were sampled from selected horizons for determining particle size distributions, water retention curves, and pore geometry, respectively. Pore shape and size were determined from binary images obtained from resin-impregnated blocks and used to characterize pore geometry. Soil water contents were recorded at a 20-minute interval over a 4-month period. The Mexican hat wavelet was used to decompose soil water content measurements into wavelet components. The responses of wavelet components to wetting and drying cycles were characterized by the median height of the peaks in each wavelet component and were correlated with particular pore shapes and sizes. For instance, large elongated and irregular pores, largely responsible for the transmission of water, were significantly correlated with wavelet components at high frequencies (40 minutes to 48 hours) while rounded pores, typically associated to water retention, were only significantly correlated to lower frequency ranges

IP3-mediated gating mechanism of the IP3 receptor revealed by mutagenesis and X-ray crystallography.

PubMed

Hamada, Kozo; Miyatake, Hideyuki; Terauchi, Akiko; Mikoshiba, Katsuhiko

2017-05-02

The inositol 1,4,5-trisphosphate (IP 3 ) receptor (IP 3 R) is an IP 3 -gated ion channel that releases calcium ions (Ca 2+ ) from the endoplasmic reticulum. The IP 3 -binding sites in the large cytosolic domain are distant from the Ca 2+ conducting pore, and the allosteric mechanism of how IP 3 opens the Ca 2+ channel remains elusive. Here, we identify a long-range gating mechanism uncovered by channel mutagenesis and X-ray crystallography of the large cytosolic domain of mouse type 1 IP 3 R in the absence and presence of IP 3 Analyses of two distinct space group crystals uncovered an IP 3 -dependent global translocation of the curvature α-helical domain interfacing with the cytosolic and channel domains. Mutagenesis of the IP 3 R channel revealed an essential role of a leaflet structure in the α-helical domain. These results suggest that the curvature α-helical domain relays IP 3 -controlled global conformational dynamics to the channel through the leaflet, conferring long-range allosteric coupling from IP 3 binding to the Ca 2+ channel.

IP3-mediated gating mechanism of the IP3 receptor revealed by mutagenesis and X-ray crystallography

PubMed Central

Hamada, Kozo; Miyatake, Hideyuki; Terauchi, Akiko; Mikoshiba, Katsuhiko

2017-01-01

The inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) is an IP3-gated ion channel that releases calcium ions (Ca2+) from the endoplasmic reticulum. The IP3-binding sites in the large cytosolic domain are distant from the Ca2+ conducting pore, and the allosteric mechanism of how IP3 opens the Ca2+ channel remains elusive. Here, we identify a long-range gating mechanism uncovered by channel mutagenesis and X-ray crystallography of the large cytosolic domain of mouse type 1 IP3R in the absence and presence of IP3. Analyses of two distinct space group crystals uncovered an IP3-dependent global translocation of the curvature α-helical domain interfacing with the cytosolic and channel domains. Mutagenesis of the IP3R channel revealed an essential role of a leaflet structure in the α-helical domain. These results suggest that the curvature α-helical domain relays IP3-controlled global conformational dynamics to the channel through the leaflet, conferring long-range allosteric coupling from IP3 binding to the Ca2+ channel. PMID:28416699

Site-Directed Spin Labeling Reveals Pentameric Ligand-Gated Ion Channel Gating Motions

PubMed Central

Dellisanti, Cosma D.; Ghosh, Borna; Hanson, Susan M.; Raspanti, James M.; Grant, Valerie A.; Diarra, Gaoussou M.; Schuh, Abby M.; Satyshur, Kenneth; Klug, Candice S.; Czajkowski, Cynthia

2013-01-01

Pentameric ligand-gated ion channels (pLGICs) are neurotransmitter-activated receptors that mediate fast synaptic transmission. In pLGICs, binding of agonist to the extracellular domain triggers a structural rearrangement that leads to the opening of an ion-conducting pore in the transmembrane domain and, in the continued presence of neurotransmitter, the channels desensitize (close). The flexible loops in each subunit that connect the extracellular binding domain (loops 2, 7, and 9) to the transmembrane channel domain (M2–M3 loop) are essential for coupling ligand binding to channel gating. Comparing the crystal structures of two bacterial pLGIC homologues, ELIC and the proton-activated GLIC, suggests channel gating is associated with rearrangements in these loops, but whether these motions accurately predict the motions in functional lipid-embedded pLGICs is unknown. Here, using site-directed spin labeling (SDSL) electron paramagnetic resonance (EPR) spectroscopy and functional GLIC channels reconstituted into liposomes, we examined if, and how far, the loops at the ECD/TMD gating interface move during proton-dependent gating transitions from the resting to desensitized state. Loop 9 moves ∼9 Å inward toward the channel lumen in response to proton-induced desensitization. Loop 9 motions were not observed when GLIC was in detergent micelles, suggesting detergent solubilization traps the protein in a nonactivatable state and lipids are required for functional gating transitions. Proton-induced desensitization immobilizes loop 2 with little change in position. Proton-induced motion of the M2–M3 loop was not observed, suggesting its conformation is nearly identical in closed and desensitized states. Our experimentally derived distance measurements of spin-labeled GLIC suggest ELIC is not a good model for the functional resting state of GLIC, and that the crystal structure of GLIC does not correspond to a desensitized state. These findings advance our

Activation gating kinetics of GIRK channels are mediated by cytoplasmic residues adjacent to transmembrane domains.

PubMed

Sadja, Rona; Reuveny, Eitan

2009-01-01

G-protein-coupled inwardly rectifying potassium channels (GIRK/Kir3.x) are involved in neurotransmission-mediated reduction of excitability. The gating mechanism following G protein activation of these channels likely proceeds from movement of inner transmembrane helices to allow K(+) ions movement through the pore of the channel. There is limited understanding of how the binding of G-protein betagamma subunits to cytoplasmic regions of the channel transduces the signal to the transmembrane regions. In this study, we examined the molecular basis that governs the activation kinetics of these channels, using a chimeric approach. We identified two regions as being important in determining the kinetics of activation. One region is the bottom of the outer transmembrane helix (TM1) and the cytoplasmic domain immediately adjacent (the slide helix); and the second region is the bottom of the inner transmembrane helix (TM2) and the cytoplasmic domain immediately adjacent. Interestingly, both of these regions are sufficient in mediating the kinetics of fast activation gating. This result suggests that there is a cooperative movement of either one of these domains to allow fast and efficient activation gating of GIRK channels.

Signature and Pathophysiology of Non-canonical Pores in Voltage-Dependent Cation Channels.

PubMed

Held, Katharina; Voets, Thomas; Vriens, Joris

2016-01-01

Opening and closing of voltage-gated cation channels allows the regulated flow of cations such as Na(+), K(+), and Ca(2+) across cell membranes, which steers essential physiological processes including shaping of action potentials and triggering Ca(2+)-dependent processes. Classical textbooks describe the voltage-gated cation channels as membrane proteins with a single, central aqueous pore. In recent years, however, evidence has accumulated for the existence of additional ion permeation pathways in this group of cation channels, distinct from the central pore, which here we collectively name non-canonical pores. Whereas the first non-canonical pores were unveiled only after making specific point mutations in the voltage-sensor region of voltage-gated Na(+) and K(+) channels, recent evidence indicates that they may also be functional in non-mutated channels. Moreover, several channelopathies have been linked to mutations that cause the appearance of a non-canonical ion permeation pathway as a new pathological mechanism. This review provides an integrated overview of the biophysical properties of non-canonical pores described in voltage-dependent cation channels (KV, NaV, Cav, Hv1, and TRPM3) and of the (patho)physiological impact of opening of such pores.

Non-scaling behavior of electroosmotic flow in voltage-gated nanopores

DOE PAGES

Lian, Cheng; Gallegos, Alejandro; Liu, Honglai; ...

2016-11-17

Ionic transport through nanopores is of fundamental importance for the design and development of nanofiltration membranes and novel electrochemical devices including supercapacitors, fuel cells and batteries. Recent experiments have shown an unusual variation of electrical conductance with the pore size and the electrolyte parameters that defies conventional scaling relations. Here ionic transport through voltage-gated nanopores was studied by using the classical density functional theory for ion distributions in combination with the Navier–Stokes equation for the electroosmotic flow. We also identified a significant influence of the gating potential on the scaling behavior of the conductance with changes in the pore sizemore » and the salt concentration. Finally, for ion transport in narrow pores with a high gating voltage, the conductivity shows an oscillatory dependence on the pore size owing to the strong overlap of electric double layers.« less

Unlocking the Physiochemical Controls on Organic Carbon Dynamics from the Soil Pore- to Core-Scale

NASA Astrophysics Data System (ADS)

Smith, A. P.; Tfaily, M. M.; Bond-Lamberty, B. P.; Todd-Brown, K. E.; Bailey, V. L.

2015-12-01

The physical organization of soil includes pore networks of varying size and connectivity. These networks control microbial access to soil organic carbon (C) by spatially separating microorganisms and C by both distance and size exclusion. The extent to which this spatially isolated C is vulnerable to microbial transformation under hydrologically dynamic conditions is unknown, and limits our ability to predict the source and sink capacity of soils. We investigated the effects of shifting hydrologic connectivity and soil structure on greenhouse gas C emissions from surface soils collected from the Disney Wilderness Preserve (Florida, USA). We subjected intact soil cores and re-packed homogenized soil cores to simulated groundwater rise or precipitation, monitoring their CO2 and CH4 emissions over 24 hours. Soil pore water was then extracted from each core using different suctions to sample water retained by pore throats of different sizes and then characterized by Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry. Greater respiration rates were observed from homogenized cores compared to intact cores, and from soils wet from below, in which the wetting front is driven by capillary forces, filling fine pores first. This suggests that C located in fine pores may turn over via diffusion processes that lead to the colocation of this C with other resources and microorganisms. Both the complexity and concentration of soluble-C increased with decreasing pore size domains. Pore water extracted from homogenized cores had greater C concentrations than from intact cores, with the greatest concentrations in pore waters sampled from very fine pores, highlighting the importance of soil structure in physically protecting C. These results suggest that the spatial separation of decomposers from C is a key mechanism stabilizing C in these soils. Further research is ongoing to accurately represent this protection mechanism, and the conditions under which it breaks

Pore-scale simulation of CO2-water-rock interactions

NASA Astrophysics Data System (ADS)

Deng, H.; Molins, S.; Steefel, C. I.; DePaolo, D. J.

2017-12-01

In Geologic Carbon Storage (GCS) systems, the migration of scCO2 versus CO2-acidifed brine ultimately determines the extent of mineral trapping and caprock integrity, i.e. the long-term storage efficiency and security. While continuum scale multiphase reactive transport models are valuable for large scale investigations, they typically (over-)simplify pore-scale dynamics and cannot capture local heterogeneities that may be important. Therefore, pore-scale models are needed in order to provide mechanistic understanding of how fine scale structural variations and heterogeneous processes influence the transport and geochemistry in the context of multiphase flow, and to inform parameterization of continuum scale modeling. In this study, we investigate the interplay of different processes at pore scale (e.g. diffusion, reactions, and multiphase flow) through the coupling of a well-developed multiphase flow simulator with a sophisticated reactive transport code. The objectives are to understand where brine displaced by scCO2 will reside in a rough pore/fracture, and how the CO2-water-rock interactions may affect the redistribution of different phases. In addition, the coupled code will provide a platform for model testing in pore-scale multiphase reactive transport problems.

Investigating Hydrophilic Pores in Model Lipid Bilayers using Molecular Simulations: Correlating Bilayer Properties with Pore Formation Thermodynamics

PubMed Central

Hu, Yuan; Sinha, Sudipta Kumar

2015-01-01

Cell-penetrating and antimicrobial peptides show remarkable ability to translocate across physiological membranes. Along with factors such as electric potential induced-perturbations of membrane structure and surface tension effects, experiments invoke pore-like membrane configurations during the solute transfer process into vesicles and cells. The initiation and formation of pores are associated with a non-trivial free energy cost, thus necessitating consideration of the factors associated with pore formation and attendant free energetics. Due to experimental and modeling challenges related to the long timescales of the translocation process, we use umbrella-sampling molecular dynamics simulations with a lipid-density based order parameter to investigate membrane pore-formation free energy employing Martini coarse-grained models. We investigate structure and thermodynamic features of the pore in 18 lipids spanning a range of head-groups, charge states, acyl chain lengths and saturation. We probe the dependence of pore-formation barriers on area per lipid, lipid bilayer thickness, membrane bending rigidities in three different lipid classes. The pore formation free energy in pure bilayers and peptide translocating scenarios are significantly coupled with bilayer thickness. Thicker bilayers require more reversible work to create pores. Pore formation free energy is higher in peptide-lipid systems relative to the peptide-free lipid systems due to penalties to maintain solvation of charged hydrophilic solutes within the membrane environment. PMID:25614183

Modulation of BK channel voltage gating by different auxiliary β subunits

PubMed Central

Contreras, Gustavo F.; Neely, Alan; Alvarez, Osvaldo; Gonzalez, Carlos; Latorre, Ramon

2012-01-01

Calcium- and voltage-activated potassium channels (BK) are regulated by a multiplicity of signals. The prevailing view is that different BK gating mechanisms converge to determine channel opening and that these gating mechanisms are allosterically coupled. In most instances the pore forming α subunit of BK is associated with one of four alternative β subunits that appear to target specific gating mechanisms to regulate the channel activity. In particular, β1 stabilizes the active configuration of the BK voltage sensor having a large effect on BK Ca2+ sensitivity. To determine the extent to which β subunits regulate the BK voltage sensor, we measured gating currents induced by the pore-forming BK α subunit alone and with the different β subunits expressed in Xenopus oocytes (β1, β2IR, β3b, and β4). We found that β1, β2, and β4 stabilize the BK voltage sensor in the active conformation. β3 has no effect on voltage sensor equilibrium. In addition, β4 decreases the apparent number of charges per voltage sensor. The decrease in the charge associated with the voltage sensor in α β4 channels explains most of their biophysical properties. For channels composed of the α subunit alone, gating charge increases slowly with pulse duration as expected if a significant fraction of this charge develops with a time course comparable to that of K+ current activation. In the presence of β1, β2, and β4 this slow component develops in advance of and much more rapidly than ion current activation, suggesting that BK channel opening proceeds in two steps. PMID:23112204

Tuning the allosteric regulation of artificial muscarinic and dopaminergic ligand-gated potassium channels by protein engineering of G protein-coupled receptors

PubMed Central

Moreau, Christophe J.; Revilloud, Jean; Caro, Lydia N.; Dupuis, Julien P.; Trouchet, Amandine; Estrada-Mondragón, Argel; Nieścierowicz, Katarzyna; Sapay, Nicolas; Crouzy, Serge; Vivaudou, Michel

2017-01-01

Ligand-gated ion channels enable intercellular transmission of action potential through synapses by transducing biochemical messengers into electrical signal. We designed artificial ligand-gated ion channels by coupling G protein-coupled receptors to the Kir6.2 potassium channel. These artificial channels called ion channel-coupled receptors offer complementary properties to natural channels by extending the repertoire of ligands to those recognized by the fused receptors, by generating more sustained signals and by conferring potassium selectivity. The first artificial channels based on the muscarinic M2 and the dopaminergic D2L receptors were opened and closed by acetylcholine and dopamine, respectively. We find here that this opposite regulation of the gating is linked to the length of the receptor C-termini, and that C-terminus engineering can precisely control the extent and direction of ligand gating. These findings establish the design rules to produce customized ligand-gated channels for synthetic biology applications. PMID:28145461

Unfolding of a Temperature-Sensitive Domain Controls Voltage-Gated Channel Activation.

PubMed

Arrigoni, Cristina; Rohaim, Ahmed; Shaya, David; Findeisen, Felix; Stein, Richard A; Nurva, Shailika Reddy; Mishra, Smriti; Mchaourab, Hassane S; Minor, Daniel L

2016-02-25

Voltage-gated ion channels (VGICs) are outfitted with diverse cytoplasmic domains that impact function. To examine how such elements may affect VGIC behavior, we addressed how the bacterial voltage-gated sodium channel (BacNa(V)) C-terminal cytoplasmic domain (CTD) affects function. Our studies show that the BacNa(V) CTD exerts a profound influence on gating through a temperature-dependent unfolding transition in a discrete cytoplasmic domain, the neck domain, proximal to the pore. Structural and functional studies establish that the BacNa(V) CTD comprises a bi-partite four-helix bundle that bears an unusual hydrophilic core whose integrity is central to the unfolding mechanism and that couples directly to the channel activation gate. Together, our findings define a general principle for how the widespread four-helix bundle cytoplasmic domain architecture can control VGIC responses, uncover a mechanism underlying the diverse BacNa(V) voltage dependencies, and demonstrate that a discrete domain can encode the temperature-dependent response of a channel. Copyright © 2016 Elsevier Inc. All rights reserved.

Role of the Outer Pore Domain in Transient Receptor Potential Vanilloid 1 Dynamic Permeability to Large Cations*

PubMed Central

Munns, Clare H.; Chung, Man-Kyo; Sanchez, Yuly E.; Amzel, L. Mario; Caterina, Michael J.

2015-01-01

Transient receptor potential vanilloid 1 (TRPV1) has been shown to alter its ionic selectivity profile in a time- and agonist-dependent manner. One hallmark of this dynamic process is an increased permeability to large cations such as N-methyl-d-glucamine (NMDG). In this study, we mutated residues throughout the TRPV1 pore domain to identify loci that contribute to dynamic large cation permeability. Using resiniferatoxin (RTX) as the agonist, we identified multiple gain-of-function substitutions within the TRPV1 pore turret (N628P and S629A), pore helix (F638A), and selectivity filter (M644A) domains. In all of these mutants, maximum NMDG permeability was substantially greater than that recorded in wild type TRPV1, despite similar or even reduced sodium current density. Two additional mutants, located in the pore turret (G618W) and selectivity filter (M644I), resulted in significantly reduced maximum NMDG permeability. M644A and M644I also showed increased and decreased minimum NMDG permeability, respectively. The phenotypes of this panel of mutants were confirmed by imaging the RTX-evoked uptake of the large cationic fluorescent dye YO-PRO1. Whereas none of the mutations selectively altered capsaicin-induced changes in NMDG permeability, the loss-of-function phenotypes seen with RTX stimulation of G618W and M644I were recapitulated in the capsaicin-evoked YO-PRO1 uptake assay. Curiously, the M644A substitution resulted in a loss, rather than a gain, in capsaicin-evoked YO-PRO1 uptake. Modeling of our mutations onto the recently determined TRPV1 structure revealed several plausible mechanisms for the phenotypes observed. We conclude that side chain interactions at a few specific loci within the TRPV1 pore contribute to the dynamic process of ionic selectivity. PMID:25568328

Role of the outer pore domain in transient receptor potential vanilloid 1 dynamic permeability to large cations.

PubMed

Munns, Clare H; Chung, Man-Kyo; Sanchez, Yuly E; Amzel, L Mario; Caterina, Michael J

2015-02-27

Transient receptor potential vanilloid 1 (TRPV1) has been shown to alter its ionic selectivity profile in a time- and agonist-dependent manner. One hallmark of this dynamic process is an increased permeability to large cations such as N-methyl-D-glucamine (NMDG). In this study, we mutated residues throughout the TRPV1 pore domain to identify loci that contribute to dynamic large cation permeability. Using resiniferatoxin (RTX) as the agonist, we identified multiple gain-of-function substitutions within the TRPV1 pore turret (N628P and S629A), pore helix (F638A), and selectivity filter (M644A) domains. In all of these mutants, maximum NMDG permeability was substantially greater than that recorded in wild type TRPV1, despite similar or even reduced sodium current density. Two additional mutants, located in the pore turret (G618W) and selectivity filter (M644I), resulted in significantly reduced maximum NMDG permeability. M644A and M644I also showed increased and decreased minimum NMDG permeability, respectively. The phenotypes of this panel of mutants were confirmed by imaging the RTX-evoked uptake of the large cationic fluorescent dye YO-PRO1. Whereas none of the mutations selectively altered capsaicin-induced changes in NMDG permeability, the loss-of-function phenotypes seen with RTX stimulation of G618W and M644I were recapitulated in the capsaicin-evoked YO-PRO1 uptake assay. Curiously, the M644A substitution resulted in a loss, rather than a gain, in capsaicin-evoked YO-PRO1 uptake. Modeling of our mutations onto the recently determined TRPV1 structure revealed several plausible mechanisms for the phenotypes observed. We conclude that side chain interactions at a few specific loci within the TRPV1 pore contribute to the dynamic process of ionic selectivity. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Threading dynamics of a polymer through parallel pores: Potential applications to DNA size separation

NASA Astrophysics Data System (ADS)

Åkerman, Björn

1997-04-01

DNA orientation measurements by linear dichroism (LD) spectroscopy and single molecule imaging by fluorescence microscopy are used to investigate the effect of DNA size (71-740 kilo base pairs) and field strength E (1-5.9 V/cm) on the conformation dynamics during the field-driven threading of DNA molecules through a set of parallel pores in agarose gels, with average pore radii between 380 Å and 1400 Å. Locally relaxed but globally oriented DNA molecules are subjected to a perpendicular field, and the observed LD time profile is compared with a recent theory for the threading [D. Long and J.-L. Viovy, Phys. Rev. E 53, 803 (1996)] which assumes the same initial state. As predicted the DNA is driven by the ends into a U-form, leading to an overshoot in the LD. The overshoot-time scales as E-(1.2-1.4) as predicted, but grows more slowly with DNA size than the predicted linear dependence. For long molecules loops form initially in the threading process but are finally consumed by the ends, and the process of transfer of DNA segments, from the loops to the arms of the U, leads to a shoulder in the LD as predicted. The critical size below which loops do not form (as indicated by the LD shoulder being absent) is between 71 and 105 kbp (0.5% agarose, 5.9 V/cm), and considerably larger than predicted because in the initial state the DNA molecules are housed in gel cavities with effective pore sizes about four times larger than the average pore size. From the data, the separation of DNA by exploiting the threading dynamics in pulsed fields [D. Long et al., CR Acad. Sci. Paris, Ser. IIb 321, 239 (1995)] is shown to be feasible in principle in an agarose-based system.

Protected quantum computing: interleaving gate operations with dynamical decoupling sequences.

PubMed

Zhang, Jingfu; Souza, Alexandre M; Brandao, Frederico Dias; Suter, Dieter

2014-02-07

Implementing precise operations on quantum systems is one of the biggest challenges for building quantum devices in a noisy environment. Dynamical decoupling attenuates the destructive effect of the environmental noise, but so far, it has been used primarily in the context of quantum memories. Here, we experimentally demonstrate a general scheme for combining dynamical decoupling with quantum logical gate operations using the example of an electron-spin qubit of a single nitrogen-vacancy center in diamond. We achieve process fidelities >98% for gate times that are 2 orders of magnitude longer than the unprotected dephasing time T2.

Four Ca2+ Ions Activate TRPM2 Channels by Binding in Deep Crevices near the Pore but Intracellularly of the Gate

PubMed Central

Törőcsik, Beáta

2009-01-01

TRPM2 is a tetrameric Ca2+-permeable channel involved in immunocyte respiratory burst and in postischaemic neuronal death. In whole cells, TRPM2 activity requires intracellular ADP ribose (ADPR) and intra- or extracellular Ca2+, but the mechanism and the binding sites for Ca2+ activation remain unknown. Here we study TRPM2 gating in inside-out patches while directly controlling intracellular ligand concentrations. Concentration jump experiments at various voltages and Ca2+ dependence of steady-state single-channel gating kinetics provide unprecedented insight into the molecular mechanism of Ca2+ activation. In patches excised from Xenopus laevis oocytes expressing human TRPM2, coapplication of intracellular ADPR and Ca2+ activated ∼50-pS nonselective cation channels; K1/2 for ADPR was ∼1 µM at saturating Ca2+. Intracellular Ca2+ dependence of TRPM2 steady-state opening and closing rates (at saturating [ADPR] and low extracellular Ca2+) reveals that Ca2+ activation is a consequence of tighter binding of Ca2+ in the open rather than in the closed channel conformation. Four Ca2+ ions activate TRPM2 with a Monod-Wymann-Changeux mechanism: each binding event increases the open-closed equilibrium constant ∼33-fold, producing altogether 106-fold activation. Experiments in the presence of 1 mM of free Ca2+ on the extracellular side clearly show that closed channels do not sense extracellular Ca2+, but once channels have opened Ca2+ entering passively through the pore slows channel closure by keeping the “activating sites” saturated, despite rapid continuous Ca2+-free wash of the intracellular channel surface. This effect of extracellular Ca2+ on gating is gradually lost at progressively depolarized membrane potentials, where the driving force for Ca2+ influx is diminished. Thus, the activating sites lie intracellularly from the gate, but in a shielded crevice near the pore entrance. Our results suggest that in intact cells that contain micromolar ADPR a single

A characterization of the coupled evolution of grain fabric and pore space using complex networks: Pore connectivity and optimized flows in the presence of shear bands

NASA Astrophysics Data System (ADS)

Russell, Scott; Walker, David M.; Tordesillas, Antoinette

2016-03-01

A framework for the multiscale characterization of the coupled evolution of the solid grain fabric and its associated pore space in dense granular media is developed. In this framework, a pseudo-dual graph transformation of the grain contact network produces a graph of pores which can be readily interpreted as a pore space network. Survivability, a new metric succinctly summarizing the connectivity of the solid grain and pore space networks, measures material robustness. The size distribution and the connectivity of pores can be characterized quantitatively through various network properties. Assortativity characterizes the pore space with respect to the parity of the number of particles enclosing the pore. Multiscale clusters of odd parity versus even parity contact cycles alternate spatially along the shear band: these represent, respectively, local jamming and unjamming regions that continually switch positions in time throughout the failure regime. Optimal paths, established using network shortest paths in favor of large pores, provide clues on preferential paths for interstitial matter transport. In systems with higher rolling resistance at contacts, less tortuous shortest paths thread through larger pores in shear bands. Notably the structural patterns uncovered in the pore space suggest that more robust models of interstitial pore flow through deforming granular systems require a proper consideration of the evolution of in situ shear band and fracture patterns - not just globally, but also inside these localized failure zones.

Coupled intertwiner dynamics: A toy model for coupling matter to spin foam models

NASA Astrophysics Data System (ADS)

Steinhaus, Sebastian

2015-09-01

The universal coupling of matter and gravity is one of the most important features of general relativity. In quantum gravity, in particular spin foams, matter couplings have been defined in the past, yet the mutual dynamics, in particular if matter and gravity are strongly coupled, are hardly explored, which is related to the definition of both matter and gravitational degrees of freedom on the discretization. However, extracting these mutual dynamics is crucial in testing the viability of the spin foam approach and also establishing connections to other discrete approaches such as lattice gauge theories. Therefore, we introduce a simple two-dimensional toy model for Yang-Mills coupled to spin foams, namely an Ising model coupled to so-called intertwiner models defined for SU (2 )k. The two systems are coupled by choosing the Ising coupling constant to depend on spin labels of the background, as these are interpreted as the edge lengths of the discretization. We coarse grain this toy model via tensor network renormalization and uncover an interesting dynamics: the Ising phase transition temperature turns out to be sensitive to the background configurations and conversely, the Ising model can induce phase transitions in the background. Moreover, we observe a strong coupling of both systems if close to both phase transitions.

Molecular Dynamic Simulation of Water Vapor and Determination of Diffusion Characteristics in the Pore

NASA Astrophysics Data System (ADS)

Nikonov, Eduard G.; Pavluš, Miron; Popovičová, Mária

2018-02-01

One of the varieties of pores, often found in natural or artificial building materials, are the so-called blind pores of dead-end or saccate type. Three-dimensional model of such kind of pore has been developed in this work. This model has been used for simulation of water vapor interaction with individual pore by molecular dynamics in combination with the diffusion equation method. Special investigations have been done to find dependencies between thermostats implementations and conservation of thermodynamic and statistical values of water vapor - pore system. The two types of evolution of water - pore system have been investigated: drying and wetting of the pore. Full research of diffusion coefficient, diffusion velocity and other diffusion parameters has been made.

Investigating Hydrophilic Pores in Model Lipid Bilayers Using Molecular Simulations: Correlating Bilayer Properties with Pore-Formation Thermodynamics.

PubMed

Hu, Yuan; Sinha, Sudipta Kumar; Patel, Sandeep

2015-06-23

Cell-penetrating and antimicrobial peptides show a remarkable ability to translocate across physiological membranes. Along with factors such as electric-potential-induced perturbations of membrane structure and surface tension effects, experiments invoke porelike membrane configurations during the solute transfer process into vesicles and cells. The initiation and formation of pores are associated with a nontrivial free-energy cost, thus necessitating a consideration of the factors associated with pore formation and the attendant free energies. Because of experimental and modeling challenges related to the long time scales of the translocation process, we use umbrella sampling molecular dynamics simulations with a lipid-density-based order parameter to investigate membrane-pore-formation free energy employing Martini coarse-grained models. We investigate structure and thermodynamic features of the pore in 18 lipids spanning a range of headgroups, charge states, acyl chain lengths, and saturation. We probe the dependence of pore-formation barriers on the area per lipid, lipid bilayer thickness, and membrane bending rigidities in three different lipid classes. The pore-formation free energy in pure bilayers and peptide translocating scenarios are significantly coupled with bilayer thickness. Thicker bilayers require more reversible work to create pores. The pore-formation free energy is higher in peptide-lipid systems than in peptide-free lipid systems due to penalties to maintain the solvation of charged hydrophilic solutes within the membrane environment.

A conserved mechanism for gating in an ionotropic glutamate receptor.

PubMed

Moore, Bryn S; Mirshahi, Uyenlinh L; Ebersole, Tonya L; Mirshahi, Tooraj

2013-06-28

Ionotropic glutamate receptor (iGluR) channels control synaptic activity. The crystallographic structure of GluA2, the prototypical iGluR, reveals a clamshell-like ligand-binding domain (LBD) that closes in the presence of glutamate to open a gate on the pore lining α-helix. How LBD closure leads to gate opening remains unclear. Here, we show that bending the pore helix at a highly conserved alanine residue (Ala-621) below the gate is responsible for channel opening. Substituting Ala-621 with the smaller more flexible glycine resulted in a basally active, nondesensitizing channel with ∼39-fold increase in glutamate potency without affecting surface expression or binding. On GluA2(A621G), the partial agonist kainate showed efficacy similar to a full agonist, and competitive antagonists CNQX and DNQX acted as a partial agonists. Met-629 in GluA2 sits above the gate and is critical in transmitting LBD closure to the gate. Substituting Met-629 with the flexible glycine resulted in reduced channel activity and glutamate potency. The pore regions in potassium channels are structurally similar to iGluRs. Whereas potassium channels typically use glycines as a hinge for gating, iGluRs use the less flexible alanine as a hinge at a similar position to maintain low basal activity allowing for ligand-mediated gating.

Sequential interaction of chloride and proton ions with the fast gate steer the voltage-dependent gating in ClC-2 chloride channels

PubMed Central

Sánchez-Rodríguez, Jorge E; De Santiago-Castillo, José A; Contreras-Vite, Juan Antonio; Nieto-Delgado, Pablo G; Castro-Chong, Alejandra; Arreola, Jorge

2012-01-01

The interaction of either H+ or Cl− ions with the fast gate is the major source of voltage (Vm) dependence in ClC Cl− channels. However, the mechanism by which these ions confer Vm dependence to the ClC-2 Cl− channel remains unclear. By determining the Vm dependence of normalized conductance (Gnorm(Vm)), an index of open probability, ClC-2 gating was studied at different [H+]i, [H+]o and [Cl−]i. Changing [H+]i by five orders of magnitude whilst [Cl−]i/[Cl−]o = 140/140 or 10/140 mm slightly shifted Gnorm(Vm) to negative Vm without altering the onset kinetics; however, channel closing was slower at acidic pHi. A similar change in [H+]o with [Cl−]i/[Cl−]o = 140/140 mm enhanced Gnorm in a bell-shaped manner and shifted Gnorm(Vm) curves to positive Vm. Importantly, Gnorm was >0 with [H+]o = 10−10 m but channel closing was slower when [H+]o or [Cl−]i increased implying that ClC-2 was opened without protonation and that external H+ and/or internal Cl− ions stabilized the open conformation. The analysis of kinetics and steady-state properties at different [H+]o and [Cl−]i was carried out using a gating Scheme coupled to Cl− permeation. Unlike previous results showing Vm-dependent protonation, our analysis revealed that fast gate protonation was Vm and Cl− independent and the equilibrium constant for closed–open transition of unprotonated channels was facilitated by elevated [Cl−]i in a Vm-dependent manner. Hence a Vm dependence of pore occupancy by Cl− induces a conformational change in unprotonated closed channels, before the pore opens, and the open conformation is stabilized by Cl− occupancy and Vm-independent protonation. PMID:22753549

Pore-scale dynamics of salt transport and distribution in drying porous media

NASA Astrophysics Data System (ADS)

Shokri, Nima

2014-01-01

Understanding the physics of water evaporation from saline porous media is important in many natural and engineering applications such as durability of building materials and preservation of monuments, water quality, and mineral-fluid interactions. We applied synchrotron x-ray micro-tomography to investigate the pore-scale dynamics of dissolved salt distribution in a three dimensional drying saline porous media using a cylindrical plastic column (15 mm in height and 8 mm in diameter) packed with sand particles saturated with CaI2 solution (5% concentration by mass) with a spatial and temporal resolution of 12 μm and 30 min, respectively. Every time the drying sand column was set to be imaged, two different images were recorded using distinct synchrotron x-rays energies immediately above and below the K-edge value of Iodine. Taking the difference between pixel gray values enabled us to delineate the spatial and temporal distribution of CaI2 concentration at pore scale. Results indicate that during early stages of evaporation, air preferentially invades large pores at the surface while finer pores remain saturated and connected to the wet zone at bottom via capillary-induced liquid flow acting as evaporating spots. Consequently, the salt concentration increases preferentially in finer pores where evaporation occurs. Higher salt concentration was observed close to the evaporating surface indicating a convection-driven process. The obtained salt profiles were used to evaluate the numerical solution of the convection-diffusion equation (CDE). Results show that the macro-scale CDE could capture the overall trend of the measured salt profiles but fail to produce the exact slope of the profiles. Our results shed new insight on the physics of salt transport and its complex dynamics in drying porous media and establish synchrotron x-ray tomography as an effective tool to investigate the dynamics of salt transport in porous media at high spatial and temporal resolution.

Aqueous Viscosity Is the Primary Source of Friction in Lipidic Pore Dynamics

PubMed Central

Ryham, Rolf; Berezovik, Irina; Cohen, Fredric S.

2011-01-01

A new theory, to our knowledge, is developed that describes the dynamics of a lipidic pore in a liposome. The equations of the theory capture the experimentally observed three-stage functional form of pore radius over time—stage 1, rapid pore enlargement; stage 2, slow pore shrinkage; and stage 3, rapid pore closure. They also show that lipid flow is kinetically limited by the values of both membrane and aqueous viscosity; therefore, pore evolution is affected by both viscosities. The theory predicts that for a giant liposome, tens of microns in radius, water viscosity dominates over the effects of membrane viscosity. The edge tension of a lipidic pore is calculated by using the theory to quantitatively account for pore kinetics in stage 3, rapid pore closing. This value of edge tension agrees with the value as standardly calculated from the stage of slow pore closure, stage 2. For small, submicron liposomes, membrane viscosity affects pore kinetics, but only if the viscosity of the aqueous solution is comparable to that of distilled water. A first-principle fluid-mechanics calculation of the friction due to aqueous viscosity is in excellent agreement with the friction obtained by applying the new theory to data of previously published experimental results. PMID:22208191

Low-photon-number optical switch and AND/OR logic gates based on quantum dot-bimodal cavity coupling system.

PubMed

Ma, Shen; Ye, Han; Yu, Zhong-Yuan; Zhang, Wen; Peng, Yi-Wei; Cheng, Xiang; Liu, Yu-Min

2016-01-11

We propose a new scheme based on quantum dot-bimodal cavity coupling system to realize all-optical switch and logic gates in low-photon-number regime. Suppression of mode transmission due to the destructive interference effect is theoretically demonstrated by driving the cavity with two orthogonally polarized pulsed lasers at certain pulse delay. The transmitted mode can be selected by designing laser pulse sequence. The optical switch with high on-off ratio emerges when considering one driving laser as the control. Moreover, the AND/OR logic gates based on photon polarization are achieved by cascading the coupling system. Both proposed optical switch and logic gates work well in ultra-low energy magnitude. Our work may enable various applications of all-optical computing and quantum information processing.

Molecular dynamics study of ion transport through an open model of voltage-gated sodium channel.

PubMed

Li, Yang; Sun, Ruining; Liu, Huihui; Gong, Haipeng

2017-05-01

Voltage-gated sodium (Na V ) channels are critical in the signal transduction of excitable cells. In this work, we modeled the open conformation for the pore domain of a prokaryotic Na V channel (Na V Rh), and used molecular dynamics simulations to track the translocation of dozens of Na + ions through the channel in the presence of a physiological transmembrane ion concentration gradient and a transmembrane electrical field that was closer to the physiological one than previous studies. Channel conductance was then estimated from simulations on the wide-type and DEKA mutant of Na V Rh. Interestingly, the conductivity predicted from the DEKA mutant agrees well with experimental measurement on eukaryotic Na V 1.4 channel. Moreover, the wide-type and DEKA mutant of Na V Rh exhibited markedly distinct ion permeation patterns, which thus implies the mechanistic difference between prokaryotic and eukaryotic Na V channels. Copyright © 2017 Elsevier B.V. All rights reserved.

The external pore loop interacts with S6 and S3-S4 linker in domain 4 to assume an essential role in gating control and anticonvulsant action in the Na+ channel

PubMed Central

Yang, Ya-Chin; Hsieh, Jui-Yi

2009-01-01

Carbamazepine, phenytoin, and lamotrigine are widely prescribed anticonvulsants in neurological clinics. These drugs bind to the same receptor site, probably with the diphenyl motif in their structure, to inhibit the Na+ channel. However, the location of the drug receptor remains controversial. In this study, we demonstrate close proximity and potential interaction between an external aromatic residue (W1716 in the external pore loop) and an internal aromatic residue (F1764 in the pore-lining part of the sixth transmembrane segment, S6) of domain 4 (D4), both being closely related to anticonvulsant and/or local anesthetic binding to the Na+ channel. Double-mutant cycle analysis reveals significant cooperativity between the two phenyl residues for anticonvulsant binding. Concomitant F1764C mutation evidently decreases the susceptibility of W1716C to external Cd2+ and membrane-impermeable methanethiosulfonate reagents. Also, the W1716E/F1764R and G1715E/F1764R double mutations significantly alter the selectivity for Na+ over K+ and markedly shift the activation curve, respectively. W1716 and F1764 therefore very likely form a link connecting the outer and inner compartments of the Na+ channel pore (in addition to the selectivity filter). Anticonvulsants and local anesthetics may well traverse this “S6 recess” without trespassing on the selectivity filter. Furthermore, we found that Y1618K, a point mutation in the S3-4 linker (the extracellular extension of D4S4), significantly alters the consequences of carbamazepine binding to the Na+ channel. The effect of Y1618K mutation, however, is abolished by concomitant point mutations in the vicinity of Y1618, but not by those in the internally located inactivation machinery, supporting a direct local rather than a long-range allosteric action. Moreover, Y1618 could interact with D4 pore residues W1716 and L1719 to have a profound effect on both channel gating and anticonvulsant action. We conclude that there are direct

The external pore loop interacts with S6 and S3-S4 linker in domain 4 to assume an essential role in gating control and anticonvulsant action in the Na(+) channel.

PubMed

Yang, Ya-Chin; Hsieh, Jui-Yi; Kuo, Chung-Chin

2009-08-01

Carbamazepine, phenytoin, and lamotrigine are widely prescribed anticonvulsants in neurological clinics. These drugs bind to the same receptor site, probably with the diphenyl motif in their structure, to inhibit the Na(+) channel. However, the location of the drug receptor remains controversial. In this study, we demonstrate close proximity and potential interaction between an external aromatic residue (W1716 in the external pore loop) and an internal aromatic residue (F1764 in the pore-lining part of the sixth transmembrane segment, S6) of domain 4 (D4), both being closely related to anticonvulsant and/or local anesthetic binding to the Na(+) channel. Double-mutant cycle analysis reveals significant cooperativity between the two phenyl residues for anticonvulsant binding. Concomitant F1764C mutation evidently decreases the susceptibility of W1716C to external Cd(2+) and membrane-impermeable methanethiosulfonate reagents. Also, the W1716E/F1764R and G1715E/F1764R double mutations significantly alter the selectivity for Na(+) over K(+) and markedly shift the activation curve, respectively. W1716 and F1764 therefore very likely form a link connecting the outer and inner compartments of the Na(+) channel pore (in addition to the selectivity filter). Anticonvulsants and local anesthetics may well traverse this "S6 recess" without trespassing on the selectivity filter. Furthermore, we found that Y1618K, a point mutation in the S3-4 linker (the extracellular extension of D4S4), significantly alters the consequences of carbamazepine binding to the Na(+) channel. The effect of Y1618K mutation, however, is abolished by concomitant point mutations in the vicinity of Y1618, but not by those in the internally located inactivation machinery, supporting a direct local rather than a long-range allosteric action. Moreover, Y1618 could interact with D4 pore residues W1716 and L1719 to have a profound effect on both channel gating and anticonvulsant action. We conclude that there

Transmembrane helical interactions in the CFTR channel pore.

PubMed

Das, Jhuma; Aleksandrov, Andrei A; Cui, Liying; He, Lihua; Riordan, John R; Dokholyan, Nikolay V

2017-06-01

Mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene affect CFTR protein biogenesis or its function as a chloride channel, resulting in dysregulation of epithelial fluid transport in the lung, pancreas and other organs in cystic fibrosis (CF). Development of pharmaceutical strategies to treat CF requires understanding of the mechanisms underlying channel function. However, incomplete 3D structural information on the unique ABC ion channel, CFTR, hinders elucidation of its functional mechanism and correction of cystic fibrosis causing mutants. Several CFTR homology models have been developed using bacterial ABC transporters as templates but these have low sequence similarity to CFTR and are not ion channels. Here, we refine an earlier model in an outward (OWF) and develop an inward (IWF) facing model employing an integrated experimental-molecular dynamics simulation (200 ns) approach. Our IWF structure agrees well with a recently solved cryo-EM structure of a CFTR IWF state. We utilize cysteine cross-linking to verify positions and orientations of residues within trans-membrane helices (TMHs) of the OWF conformation and to reconstruct a physiologically relevant pore structure. Comparison of pore profiles of the two conformations reveal a radius sufficient to permit passage of hydrated Cl- ions in the OWF but not the IWF model. To identify structural determinants that distinguish the two conformations and possible rearrangements of TMHs within them responsible for channel gating, we perform cross-linking by bifunctional reagents of multiple predicted pairs of cysteines in TMH 6 and 12 and 6 and 9. To determine whether the effects of cross-linking on gating observed are the result of switching of the channel from open to close state, we also treat the same residue pairs with monofunctional reagents in separate experiments. Both types of reagents prevent ion currents indicating that pore blockage is primarily responsible.

A chimeric prokaryotic pentameric ligand–gated channel reveals distinct pathways of activation

DOE PAGES

Schmandt, Nicolaus; Velisetty, Phanindra; Chalamalasetti, Sreevatsa V.; ...

2015-09-28

Recent high resolution structures of several pentameric ligand–gated ion channels have provided unprecedented details of their molecular architecture. However, the conformational dynamics and structural rearrangements that underlie gating and allosteric modulation remain poorly understood. We used a combination of electrophysiology, double electron–electron resonance (DEER) spectroscopy, and x-ray crystallography to investigate activation mechanisms in a novel functional chimera with the extracellular domain (ECD) of amine-gated Erwinia chrysanthemi ligand–gated ion channel, which is activated by primary amines, and the transmembrane domain of Gloeobacter violaceus ligand–gated ion channel, which is activated by protons. We found that the chimera was independently gated by primarymore » amines and by protons. The crystal structure of the chimera in its resting state, at pH 7.0 and in the absence of primary amines, revealed a closed-pore conformation and an ECD that is twisted with respect to the transmembrane region. Amine- and pH-induced conformational changes measured by DEER spectroscopy showed that the chimera exhibits a dual mode of gating that preserves the distinct conformational changes of the parent channels. Collectively, our findings shed light on both conserved and divergent features of gating mechanisms in this class of channels, and will facilitate the design of better allosteric modulators.« less

A chimeric prokaryotic pentameric ligand–gated channel reveals distinct pathways of activation

PubMed Central

Schmandt, Nicolaus; Velisetty, Phanindra; Chalamalasetti, Sreevatsa V.; Stein, Richard A.; Bonner, Ross; Talley, Lauren; Parker, Mark D.; Mchaourab, Hassane S.; Yee, Vivien C.; Lodowski, David T.

2015-01-01

Recent high resolution structures of several pentameric ligand–gated ion channels have provided unprecedented details of their molecular architecture. However, the conformational dynamics and structural rearrangements that underlie gating and allosteric modulation remain poorly understood. We used a combination of electrophysiology, double electron–electron resonance (DEER) spectroscopy, and x-ray crystallography to investigate activation mechanisms in a novel functional chimera with the extracellular domain (ECD) of amine-gated Erwinia chrysanthemi ligand–gated ion channel, which is activated by primary amines, and the transmembrane domain of Gloeobacter violaceus ligand–gated ion channel, which is activated by protons. We found that the chimera was independently gated by primary amines and by protons. The crystal structure of the chimera in its resting state, at pH 7.0 and in the absence of primary amines, revealed a closed-pore conformation and an ECD that is twisted with respect to the transmembrane region. Amine- and pH-induced conformational changes measured by DEER spectroscopy showed that the chimera exhibits a dual mode of gating that preserves the distinct conformational changes of the parent channels. Collectively, our findings shed light on both conserved and divergent features of gating mechanisms in this class of channels, and will facilitate the design of better allosteric modulators. PMID:26415570

Ionic liquid structure, dynamics, and electrosorption in carbon electrodes with bimodal pores and heterogeneous surfaces

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dyatkin, Boris; Osti, Naresh C.; Zhang, Yu

In this paper, we investigate the aggregation, diffusion, and resulting electrochemical behavior of ionic liquids inside carbon electrodes with complex pore architectures and surface chemistries. Carbide-derived carbons (CDCs) with bimodal porosities and defunctionalized or oxidized electrode surfaces served as model electrode materials. Our goal was to obtain a fundamental understanding of room-temperature ionic liquid ion orientation, mobility, and electrosorption behavior. Neat 1-octyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide confined in CDCs was studied using an integrated experimental and modeling approach, consisting of quasielastic neutron scattering, small-angle neutron scattering, X-ray pair distribution function analysis, and electrochemical measurements, which were combined with molecular dynamics simulations. Our analysismore » shows that surface oxygen groups increase the diffusion of confined electrolytes. Consequently, the ions become more than twice as mobile in oxygen-rich pores. Although greater self-diffusion of ions translates into higher electrochemical mobilities in oxidized pores, bulk-like behavior of ions dominates in the larger mesopores and increases the overall capacitance in defunctionalized pores. Experimental results highlight strong confinement and surface effects of carbon electrodes on electrolyte behavior, and molecular dynamics simulations yield insight into diffusion and capacitance differences in specific pore regions. Finally, we demonstrate the significance of surface defects on electrosorption dynamics of complex electrolytes in hierarchical pore architectures of supercapacitor electrodes.« less

Ionic liquid structure, dynamics, and electrosorption in carbon electrodes with bimodal pores and heterogeneous surfaces

DOE PAGES

Dyatkin, Boris; Osti, Naresh C.; Zhang, Yu; ...

2017-12-05

In this paper, we investigate the aggregation, diffusion, and resulting electrochemical behavior of ionic liquids inside carbon electrodes with complex pore architectures and surface chemistries. Carbide-derived carbons (CDCs) with bimodal porosities and defunctionalized or oxidized electrode surfaces served as model electrode materials. Our goal was to obtain a fundamental understanding of room-temperature ionic liquid ion orientation, mobility, and electrosorption behavior. Neat 1-octyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide confined in CDCs was studied using an integrated experimental and modeling approach, consisting of quasielastic neutron scattering, small-angle neutron scattering, X-ray pair distribution function analysis, and electrochemical measurements, which were combined with molecular dynamics simulations. Our analysismore » shows that surface oxygen groups increase the diffusion of confined electrolytes. Consequently, the ions become more than twice as mobile in oxygen-rich pores. Although greater self-diffusion of ions translates into higher electrochemical mobilities in oxidized pores, bulk-like behavior of ions dominates in the larger mesopores and increases the overall capacitance in defunctionalized pores. Experimental results highlight strong confinement and surface effects of carbon electrodes on electrolyte behavior, and molecular dynamics simulations yield insight into diffusion and capacitance differences in specific pore regions. Finally, we demonstrate the significance of surface defects on electrosorption dynamics of complex electrolytes in hierarchical pore architectures of supercapacitor electrodes.« less

Pharmacology of the Nav1.1 domain IV voltage sensor reveals coupling between inactivation gating processes.

PubMed

Osteen, Jeremiah D; Sampson, Kevin; Iyer, Vivek; Julius, David; Bosmans, Frank

2017-06-27

The Na v 1.1 voltage-gated sodium channel is a critical contributor to excitability in the brain, where pathological loss of function leads to such disorders as epilepsy, Alzheimer's disease, and autism. This voltage-gated sodium (Na v ) channel subtype also plays an important role in mechanical pain signaling by primary afferent somatosensory neurons. Therefore, pharmacologic modulation of Na v 1.1 represents a potential strategy for treating excitability disorders of the brain and periphery. Inactivation is a complex aspect of Na v channel gating and consists of fast and slow components, each of which may involve a contribution from one or more voltage-sensing domains. Here, we exploit the Hm1a spider toxin, a Na v 1.1-selective modulator, to better understand the relationship between these temporally distinct modes of inactivation and ask whether they can be distinguished pharmacologically. We show that Hm1a inhibits the gating movement of the domain IV voltage sensor (VSDIV), hindering both fast and slow inactivation and leading to an increase in Na v 1.1 availability during high-frequency stimulation. In contrast, ICA-121431, a small-molecule Na v 1.1 inhibitor, accelerates a subsequent VSDIV gating transition to accelerate entry into the slow inactivated state, resulting in use-dependent block. Further evidence for functional coupling between fast and slow inactivation is provided by a Na v 1.1 mutant in which fast inactivation removal has complex effects on slow inactivation. Taken together, our data substantiate the key role of VSDIV in Na v channel fast and slow inactivation and demonstrate that these gating processes are sequential and coupled through VSDIV. These findings provide insight into a pharmacophore on VSDIV through which modulation of inactivation gating can inhibit or facilitate Na v 1.1 function.

Ferritin contains less iron (59Fe) in cells when the protein pores are unfolded by mutation.

PubMed

Hasan, Mohammad R; Tosha, Takehiko; Theil, Elizabeth C

2008-11-14

Ferric minerals in ferritins are protected from cytoplasmic reductants and Fe2+ release by the protein nanocage until iron need is signaled. Deletion of ferritin genes is lethal; two critical ferritin functions are concentrating iron and oxidant protection (consuming cytoplasmic iron and oxygen in the mineral). In solution, opening/closing (gating) of eight ferritin protein pores controls reactions between external reductant and the ferritin mineral; pore gating is altered by mutation, low heat, and physiological urea (1 mm) and monitored by CD spectroscopy, protein crystallography, and Fe2+ release rates. To study the effects of a ferritin pore gating mutation in living cells, we cloned/expressed human ferritin H and H L138P, homologous to the frog open pore model that was unexpressable in human cells. Human ferritin H L138P behaved like the open pore ferritin model in vitro as follows: (i) normal protein cage assembly and mineralization, (ii) increased iron release (t1/2) decreased 17-fold), and (iii) decreased alpha-helix (8%). Overexpression (> 4-fold), in HeLa cells, showed for ferritin H L138P equal protein expression and total cell 59Fe but increased chelatable iron, 16%, p < 0.01 (59Fe in the deferoxamine-containing medium), and decreased 59Fe in ferritin, 28%, p < 0.01, compared with wild type. The coincidence of decreased 59Fe in open pore ferritin with increased chelatable 59Fe in cells expressing the ferritin open pore mutation suggests that ferritin pore gating influences to the amount of iron (59Fe) in ferritin in vivo.

Voltage-gated proton (H(v)1) channels, a singular voltage sensing domain.

PubMed

Castillo, Karen; Pupo, Amaury; Baez-Nieto, David; Contreras, Gustavo F; Morera, Francisco J; Neely, Alan; Latorre, Ramon; Gonzalez, Carlos

2015-11-14

The main role of voltage-gated proton channels (Hv1) is to extrude protons from the intracellular milieu when, mediated by different cellular processes, the H(+) concentration increases. Hv1 are exquisitely selective for protons and their structure is homologous to the voltage sensing domain (VSD) of other voltage-gated ion channels like sodium, potassium, and calcium channels. In clear contrast to the classical voltage-dependent channels, Hv1 lacks a pore domain and thus permeation necessarily occurs through the voltage sensing domain. Hv1 channels are activated by depolarizing voltages, and increases in internal proton concentration. It has been proposed that local conformational changes of the transmembrane segment S4, driven by depolarization, trigger the molecular rearrangements that open Hv1. However, it is still unclear how the electromechanical coupling is achieved between the VSD and the potential pore, allowing the proton flux from the intracellular to the extracellular side. Here we provide a revised view of voltage activation in Hv1 channels, offering a comparative scenario with other voltage sensing channels domains. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Analyzing and modeling the kinetics of amyloid beta pores associated with Alzheimer’s disease pathology

DOE PAGES

Ullah, Ghanim; Demuro, Angelo; Parker, Ian; ...

2015-09-08

Amyloid beta (Aβ) oligomers associated with Alzheimer’s disease (AD) form Ca 2+-permeable plasma membrane pores, leading to a disruption of the otherwise well-controlled intracellular calcium (Ca 2+) homeostasis. The resultant up-regulation of intracellular Ca 2+ concentration has detrimental implications for memory formation and cell survival. The gating kinetics and Ca 2+ permeability of Aβ pores are not well understood. We have used computational modeling in conjunction with the ability of optical patch-clamping for massively parallel imaging of Ca 2+ flux through thousands of pores in the cell membrane of Xenopus oocytes to elucidate the kinetic properties of Aβ pores. Themore » fluorescence time-series data from individual pores were idealized and used to develop data-driven Markov chain models for the kinetics of the Aβ pore at different stages of its evolution. Our study provides the first demonstration of developing Markov chain models for ion channel gating that are driven by optical-patch clamp data with the advantage of experiments being performed under close to physiological conditions. As a result, we demonstrate the up-regulation of gating of various Ca 2+ release channels due to Aβ pores and show that the extent and spatial range of such up-regulation increases as Aβ pores with low open probability and Ca 2+ permeability transition into those with high open probability and Ca 2+ permeability.« less

Nuclear Pore Complexes: Global Conservation and Local Variation.

PubMed

Holzer, Guillaume; Antonin, Wolfram

2018-06-04

Nuclear pore complexes are the transport gates to the nucleus. Most proteins forming these huge complexes are evolutionarily conserved, as is the eightfold symmetry of these complexes. A new study reporting the structure of the yeast nuclear pore complex now shows striking differences from its human counterpart. Copyright © 2018 Elsevier Ltd. All rights reserved.

Low-photon-number optical switch and AND/OR logic gates based on quantum dot-bimodal cavity coupling system

PubMed Central

Ma, Shen; Ye, Han; Yu, Zhong-Yuan; Zhang, Wen; Peng, Yi-Wei; Cheng, Xiang; Liu, Yu-Min

2016-01-01

We propose a new scheme based on quantum dot-bimodal cavity coupling system to realize all-optical switch and logic gates in low-photon-number regime. Suppression of mode transmission due to the destructive interference effect is theoretically demonstrated by driving the cavity with two orthogonally polarized pulsed lasers at certain pulse delay. The transmitted mode can be selected by designing laser pulse sequence. The optical switch with high on-off ratio emerges when considering one driving laser as the control. Moreover, the AND/OR logic gates based on photon polarization are achieved by cascading the coupling system. Both proposed optical switch and logic gates work well in ultra-low energy magnitude. Our work may enable various applications of all-optical computing and quantum information processing. PMID:26750557

Evolutionarily conserved intracellular gate of voltage-dependent sodium channels

NASA Astrophysics Data System (ADS)

Oelstrom, Kevin; Goldschen-Ohm, Marcel P.; Holmgren, Miguel; Chanda, Baron

2014-03-01

Members of the voltage-gated ion channel superfamily (VGIC) regulate ion flux and generate electrical signals in excitable cells by opening and closing pore gates. The location of the gate in voltage-gated sodium channels, a founding member of this superfamily, remains unresolved. Here we explore the chemical modification rates of introduced cysteines along the S6 helix of domain IV in an inactivation-removed background. We find that state-dependent accessibility is demarcated by an S6 hydrophobic residue; substituted cysteines above this site are not modified by charged thiol reagents when the channel is closed. These accessibilities are consistent with those inferred from open- and closed-state structures of prokaryotic sodium channels. Our findings suggest that an intracellular gate composed of a ring of hydrophobic residues is not only responsible for regulating access to the pore of sodium channels, but is also a conserved feature within canonical members of the VGIC superfamily.

Near-microsecond human aquaporin 4 gating dynamics in static and alternating external electric fields: Non-equilibrium molecular dynamics

NASA Astrophysics Data System (ADS)

English, Niall J.; Garate, José-A.

2016-08-01

An extensive suite of non-equilibrium molecular-dynamics simulation has been performed for ˜0.85-0.9 μs of human aquaporin 4 in the absence and presence of externally applied static and alternating electric fields applied along the channels (in both axial directions in the static case, taken as the laboratory z-axis). These external fields were of 0.0065 V/Å (r.m.s.) intensity (of the same order as physiological electrical potentials); alternating fields ranged in frequency from 2.45 to 500 GHz. In-pore gating dynamics was studied, particularly of the relative propensities for "open" and "closed" states of the conserved arginines in the arginine/aromatic area (itself governed in no small part by external-field response of the dipolar alignment of the histidine-201 residue in the selectivity filter). In such a manner, the intimate connection of field-response governing "two-state" histidine states was established statistically and mechanistically. Given the appreciable size of the energy barriers for histidine-201 alignment, we have also performed non-equilibrium metadynamics/local-elevation of static fields applied along both directions to construct the free-energy landscape thereof in terms of external-field direction, elucidating the importance of field direction on energetics. We conclude from direct measurement of deterministic molecular dynamics in conjunction with applied-field metadynamics that the intrinsic electric field within the channel points along the +z-axis, such that externally applied static fields in this direction serve to "open" the channel in the selectivity-filter and the asparagine-proline-alanine region.

Near-microsecond human aquaporin 4 gating dynamics in static and alternating external electric fields: Non-equilibrium molecular dynamics.

PubMed

English, Niall J; Garate, José-A

2016-08-28

An extensive suite of non-equilibrium molecular-dynamics simulation has been performed for ∼0.85-0.9 μs of human aquaporin 4 in the absence and presence of externally applied static and alternating electric fields applied along the channels (in both axial directions in the static case, taken as the laboratory z-axis). These external fields were of 0.0065 V/Å (r.m.s.) intensity (of the same order as physiological electrical potentials); alternating fields ranged in frequency from 2.45 to 500 GHz. In-pore gating dynamics was studied, particularly of the relative propensities for "open" and "closed" states of the conserved arginines in the arginine/aromatic area (itself governed in no small part by external-field response of the dipolar alignment of the histidine-201 residue in the selectivity filter). In such a manner, the intimate connection of field-response governing "two-state" histidine states was established statistically and mechanistically. Given the appreciable size of the energy barriers for histidine-201 alignment, we have also performed non-equilibrium metadynamics/local-elevation of static fields applied along both directions to construct the free-energy landscape thereof in terms of external-field direction, elucidating the importance of field direction on energetics. We conclude from direct measurement of deterministic molecular dynamics in conjunction with applied-field metadynamics that the intrinsic electric field within the channel points along the +z-axis, such that externally applied static fields in this direction serve to "open" the channel in the selectivity-filter and the asparagine-proline-alanine region.

Interlayer Coupling and Gate-Tunable Excitons in Transition Metal Dichalcogenide Heterostructures

DOE PAGES

Gao, Shiyuan; Yang, Li; Spataru, Catalin Dan

2017-11-22

Bilayer van der Waals (vdW) heterostructures such as MoS 2/WS 2 and MoSe 2/WSe 2 have attracted much attention recently, particularly because of their type II band alignments and the formation of interlayer exciton as the lowest-energy excitonic state. In this work, we calculate the electronic and optical properties of such heterostructures with the first-principles GW+Bethe–Salpeter Equation (BSE) method and reveal the important role of interlayer coupling in deciding the excited-state properties, including the band alignment and excitonic properties. Our calculation shows that due to the interlayer coupling, the low energy excitons can be widely tuned by a vertical gatemore » field. In particular, the dipole oscillator strength and radiative lifetime of the lowest energy exciton in these bilayer heterostructures is varied by over an order of magnitude within a practical external gate field. We also build a simple model that captures the essential physics behind this tunability and allows the extension of the ab initio results to a large range of electric fields. In conclusion, our work clarifies the physical picture of interlayer excitons in bilayer vdW heterostructures and predicts a wide range of gate-tunable excited-state properties of 2D optoelectronic devices.« less

Photon gating in four-dimensional ultrafast electron microscopy.

PubMed

Hassan, Mohammed T; Liu, Haihua; Baskin, John Spencer; Zewail, Ahmed H

2015-10-20

Ultrafast electron microscopy (UEM) is a pivotal tool for imaging of nanoscale structural dynamics with subparticle resolution on the time scale of atomic motion. Photon-induced near-field electron microscopy (PINEM), a key UEM technique, involves the detection of electrons that have gained energy from a femtosecond optical pulse via photon-electron coupling on nanostructures. PINEM has been applied in various fields of study, from materials science to biological imaging, exploiting the unique spatial, energy, and temporal characteristics of the PINEM electrons gained by interaction with a "single" light pulse. The further potential of photon-gated PINEM electrons in probing ultrafast dynamics of matter and the optical gating of electrons by invoking a "second" optical pulse has previously been proposed and examined theoretically in our group. Here, we experimentally demonstrate this photon-gating technique, and, through diffraction, visualize the phase transition dynamics in vanadium dioxide nanoparticles. With optical gating of PINEM electrons, imaging temporal resolution was improved by a factor of 3 or better, being limited only by the optical pulse widths. This work enables the combination of the high spatial resolution of electron microscopy and the ultrafast temporal response of the optical pulses, which provides a promising approach to attain the resolution of few femtoseconds and attoseconds in UEM.

Photon gating in four-dimensional ultrafast electron microscopy

PubMed Central

Hassan, Mohammed T.; Liu, Haihua; Baskin, John Spencer; Zewail, Ahmed H.

2015-01-01

Ultrafast electron microscopy (UEM) is a pivotal tool for imaging of nanoscale structural dynamics with subparticle resolution on the time scale of atomic motion. Photon-induced near-field electron microscopy (PINEM), a key UEM technique, involves the detection of electrons that have gained energy from a femtosecond optical pulse via photon–electron coupling on nanostructures. PINEM has been applied in various fields of study, from materials science to biological imaging, exploiting the unique spatial, energy, and temporal characteristics of the PINEM electrons gained by interaction with a “single” light pulse. The further potential of photon-gated PINEM electrons in probing ultrafast dynamics of matter and the optical gating of electrons by invoking a “second” optical pulse has previously been proposed and examined theoretically in our group. Here, we experimentally demonstrate this photon-gating technique, and, through diffraction, visualize the phase transition dynamics in vanadium dioxide nanoparticles. With optical gating of PINEM electrons, imaging temporal resolution was improved by a factor of 3 or better, being limited only by the optical pulse widths. This work enables the combination of the high spatial resolution of electron microscopy and the ultrafast temporal response of the optical pulses, which provides a promising approach to attain the resolution of few femtoseconds and attoseconds in UEM. PMID:26438835

Noise removal using factor analysis of dynamic structures: application to cardiac gated studies.

PubMed

Bruyant, P P; Sau, J; Mallet, J J

1999-10-01

Factor analysis of dynamic structures (FADS) facilitates the extraction of relevant data, usually with physiologic meaning, from a dynamic set of images. The result of this process is a set of factor images and curves plus some residual activity. The set of factor images and curves can be used to retrieve the original data with reduced noise using an inverse factor analysis process (iFADS). This improvement in image quality is expected because the inverse process does not use the residual activity, assumed to be made of noise. The goal of this work is to quantitate and assess the efficiency of this method on gated cardiac images. A computer simulation of a planar cardiac gated study was performed. The simulated images were added with noise and processed by the FADS-iFADS program. The signal-to-noise ratios (SNRs) were compared between original and processed data. Planar gated cardiac studies from 10 patients were tested. The data processed by FADS-iFADS were subtracted to the original data. The result of the substraction was studied to evaluate its noisy nature. The SNR is about five times greater after the FADS-iFADS process. The difference between original and processed data is noise only, i.e., processed data equals original data minus some white noise. The FADS-iFADS process is successful in the removal of an important part of the noise and therefore is a tool to improve the image quality of cardiac images. This tool does not decrease the spatial resolution (compared with smoothing filters) and does not lose details (compared with frequential filters). Once the number of factors is chosen, this method is not operator dependent.

Molecular Dynamics Simulations of Orai Reveal How the Third Transmembrane Segment Contributes to Hydration and Ca2+ Selectivity in Calcium Release-Activated Calcium Channels.

PubMed

Alavizargar, Azadeh; Berti, Claudio; Ejtehadi, Mohammad Reza; Furini, Simone

2018-04-26

Calcium release-activated calcium (CRAC) channels open upon depletion of Ca 2+ from the endoplasmic reticulum, and when open, they are permeable to a selective flux of calcium ions. The atomic structure of Orai, the pore domain of CRAC channels, from Drosophila melanogaster has revealed many details about conduction and selectivity in this family of ion channels. However, it is still unclear how residues on the third transmembrane helix can affect the conduction properties of the channel. Here, molecular dynamics and Brownian dynamics simulations were employed to analyze how a conserved glutamate residue on the third transmembrane helix (E262) contributes to selectivity. The comparison between the wild-type and mutated channels revealed a severe impact of the mutation on the hydration pattern of the pore domain and on the dynamics of residues K270, and Brownian dynamics simulations proved that the altered configuration of residues K270 in the mutated channel impairs selectivity to Ca 2+ over Na + . The crevices of water molecules, revealed by molecular dynamics simulations, are perfectly located to contribute to the dynamics of the hydrophobic gate and the basic gate, suggesting a possible role in channel opening and in selectivity function.

Time-Resolved Neutron Interferometry and the Mechanism of Electromechanical Coupling in Voltage-Gated Ion Channels.

PubMed

Blasie, J Kent

2018-01-01

The mechanism of electromechanical coupling for voltage-gated ion channels (VGICs) involved in neurological signal transmission, primarily Nav- and Kv-channels, remains unresolved. Anesthetics have been shown to directly impact this mechanism, at least for Kv-channels. Molecular dynamics computer simulations can now predict the structures of VGICs embedded within a hydrated phospholipid bilayer membrane as a function of the applied transmembrane voltage, but significant assumptions are still necessary. Nevertheless, these simulations are providing new insights into the mechanism of electromechanical coupling at the atomic level in 3-D. We show that time-resolved neutron interferometry can be used to investigate directly the profile structure of a VGIC, vectorially oriented within a single hydrated phospholipid bilayer membrane at the solid-liquid interface, as a function of the applied transmembrane voltage in the absence of any assumptions or potentially perturbing modifications of the VGIC protein and/or the host membrane. The profile structure is a projection of the membrane's 3-D structure onto the membrane normal and, in the absence of site-directed deuterium labeling, is provided at substantially lower spatial resolution than the atomic level. Nevertheless, this novel approach can be used to directly test the validity of the predictions from molecular dynamics simulations. We describe the key elements of our novel experimental approach, including why each is necessary and important to providing the essential information required for this critical comparison of "simulation" vs "experiment." In principle, the approach could be extended to higher spatial resolution and to include the effects of anesthetics on the electromechanical coupling mechanism in VGICs. © 2018 Elsevier Inc. All rights reserved.

Pore-scale dynamics of salt transport and distribution in drying porous media

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shokri, Nima, E-mail: nima.shokri@manchester.ac.uk

2014-01-15

Understanding the physics of water evaporation from saline porous media is important in many natural and engineering applications such as durability of building materials and preservation of monuments, water quality, and mineral-fluid interactions. We applied synchrotron x-ray micro-tomography to investigate the pore-scale dynamics of dissolved salt distribution in a three dimensional drying saline porous media using a cylindrical plastic column (15 mm in height and 8 mm in diameter) packed with sand particles saturated with CaI{sub 2} solution (5% concentration by mass) with a spatial and temporal resolution of 12 μm and 30 min, respectively. Every time the drying sandmore » column was set to be imaged, two different images were recorded using distinct synchrotron x-rays energies immediately above and below the K-edge value of Iodine. Taking the difference between pixel gray values enabled us to delineate the spatial and temporal distribution of CaI{sub 2} concentration at pore scale. Results indicate that during early stages of evaporation, air preferentially invades large pores at the surface while finer pores remain saturated and connected to the wet zone at bottom via capillary-induced liquid flow acting as evaporating spots. Consequently, the salt concentration increases preferentially in finer pores where evaporation occurs. Higher salt concentration was observed close to the evaporating surface indicating a convection-driven process. The obtained salt profiles were used to evaluate the numerical solution of the convection-diffusion equation (CDE). Results show that the macro-scale CDE could capture the overall trend of the measured salt profiles but fail to produce the exact slope of the profiles. Our results shed new insight on the physics of salt transport and its complex dynamics in drying porous media and establish synchrotron x-ray tomography as an effective tool to investigate the dynamics of salt transport in porous media at high spatial and

Structural basis of gating of CNG channels.

PubMed

Giorgetti, Alejandro; Nair, Anil V; Codega, Paolo; Torre, Vincent; Carloni, Paolo

2005-03-28

Cyclic nucleotide-gated (CNG) ion channels, underlying sensory transduction in vertebrate photoreceptors and olfactory sensory neurons, require cyclic nucleotides to open. Here, we present structural models of the tetrameric CNG channel pore from bovine rod in both open and closed states, as obtained by combining homology modeling-based techniques, experimentally derived spatial constraints and structural patterns present in the PDB database. Gating is initiated by an anticlockwise rotation of the N-terminal region of the C-linker, which is then, transmitted through the S6 transmembrane helices to the P-helix, and in turn from this to the pore lumen, which opens up from 2 to 5A thus allowing for ion permeation. The approach, here presented, is expected to provide a general methodology for model ion channels and their gating when structural templates are available and an extensive electrophysiological analysis has been performed.

Method for voltage-gated protein fractionation

DOEpatents

Hatch, Anson [Tracy, CA; Singh, Anup K [Danville, CA

2012-04-24

We report unique findings on the voltage dependence of protein exclusion from the pores of nanoporous polymer exclusion membranes. The pores are small enough that proteins are excluded from passage with low applied electric fields, but increasing the field enables proteins to pass through. The requisite field necessary for a change in exclusion is protein-specific with a correlation to protein size. The field-dependence of exclusion is important to consider for preconcentration applications. The ability to selectively gate proteins at exclusion membranes is also a promising means for manipulating and characterizing proteins. We show that field-gated exclusion can be used to selectively remove proteins from a mixture, or to selectively trap protein at one exclusion membrane in a series.

Stationary and Dynamic Permeability and Coupling Coefficient Measurements in Sintered Glass Bead Systems

NASA Astrophysics Data System (ADS)

Gueven, I.; Steeb, H.; Luding, S.

2014-12-01

Electrokinetic waves describe the coupling between seismic and electromagnetic waves that exist in porous media. The coupling between them arise from an electrochemical boundary layer between grain and fluid interface of saturated porous media. Acoustical waves cause a disturbance of the electrical fluid charge within the double layer, which therefore creates an electric streaming current (seismoelectric effect). Inversely, electromagnetic waves can generate mechanical signals (electroseismic effect). Electrokinetic conversion potentially combines high seismic resolution with good electromagnetic hydrocarbon sensitivity. The (stationary and frequency-dependent) streaming potential coefficient is a key property, which gives rise to the coupling between electromagnetic and acoustical waves. It depends strongly on the fluid conductivity, porosity, tortuosity, permeability, pore throat and zeta potential of porous media. We examine experimentally both, the stationary and dynamic permeabilities and coupling coefficients of sintered glass bead systems. For this purpose a multi-purpose measuring cell was developed which allows us to carry out - besides common ultrasound experiments - also to perform stationary and frequency-dependent permeability and coupling coefficient measurements. For the experiments sintered mono- and slightly polydisperse glass bead samples with different glass bead diameters between 0.4 and 8mm and porosities ranging between 21 and 39% were used. The stationary and dynamic permeability and streaming potential measurements are supported by μCT scans which enable us a deeper insight into the porous medium. Based on the μCT scans of the produced sintered glass bead samples essential influence parameters, like tortuosity, porosity, effective particle diameters and pore throats in different regions of the entire scanned region have been analyzed in detail to understand the laboratory experiments, cf. Illustration 1. In addition lattice Boltzmann

Dynamic properties of individual water molecules in a hydrophobic pore lined with acyl chains: a molecular dynamics study.

PubMed

Qi, Z; Sokabe, M

1998-03-30

Recently, a certain class of synthetic molecules has been shown to form ion channels, the pore of which is lined with hydrophobic acyl chains [M. Sokabe, in: F. Oosawa, H. Hayashi, T. Yoshioka (Eds.), Transmembrane Signaling and Sensation, JSSP/VNU Science Press BV, Tokyo, 1984, p. 119; F. Hayashi, M. Sokabe, M. Takagi, K. Hayashi, U. Kishimoto, Biochim. Biophys. Acta, 510 (1978) 305; M.J. Pregel, L. Jullien, J. Canceill, L. Lacombe, J.M. Lehn, J. Chem. Soc. Perkin Trans., 2 (1995) 417; Y. Tanaka, Y. Kobuke, M. Sokabe, Angew. Chem. Int. Ed. Engl., 34 (1995) 693; M. Sokabe, Z. Qi, K. Donowaki, H. Ishida, K. Okubo, Biophys. J., 70 (1996) A201; H. Ishida, K. Donowaki, Y. Inoue, Z. Qi, M. Sokabe, Chem. Lett. (1997) p. 953]. As an initial step towards understanding the physical mechanisms of ion permeation across such a hydrophobic pore, systematic molecular dynamics simulations were performed to investigate dynamic and energetic properties of water molecules inside the pore using a dimer of alanine-N'-acylated cyclic peptide as a channel model. Dynamic energy profiles for water molecules indicated that the energy barrier at the middle region of the pore is approximately 2-3 kcal/mol higher than that in the cap water region which was defined as a vicinity region of the channel entrance. Energetics analyses demonstrated that the mutual interactions among intrapore water molecules are the major factor to give favorable interaction (negative energy contribution) for themselves. The pore, despite being lined with acyl chains, has a favorable van der Waals interaction with intrapore water molecules. These results may help to explain why water-filled channels can be formed by the hydrophobic helices in natural channels.

A uniquely adaptable pore is consistent with NALCN being an ion sensor

PubMed Central

Senatore, Adriano; Spafford, J. David

2013-01-01

NALCN is an intriguing, orphan ion channel among the 4x6TM family of related voltage-gated cation channels, sharing a common architecture of four homologous domains consisting of six transmembrane helices, separated by three cytoplasmic linkers and delimited by N and C-terminal ends. NALCN is one of the shortest 4x6TM family members, lacking much of the variation that provides the diverse palate of gating features, and tissue specific adaptations of sodium and calcium channels. NALCN’s most distinctive feature is that that it possesses a highly adaptable pore with a calcium-like EEEE selectivity filter in radially symmetrical animals and a more sodium-like EEKE or EKEE selectivity filter in bilaterally symmetrical animals including vertebrates. Two lineages of animals evolved alternative calcium-like EEEE and sodium-like EEKE / EKEE pores, spliced to regulate NALCN functions in differing cellular environments, such as muscle (heart and skeletal) and secretory tissue (brain and glands), respectively. A highly adaptable pore in an otherwise conserved ion channel in the 4x6TM channel family is not consistent with a role for NALCN in directly gating a significant ion conductance that can be either sodium ions or calcium ions. NALCN was proposed to be an expressible Gd3+-sensitive, NMDG+-impermeant, non-selective and ohmic leak conductance in HEK-293T cells, but we were unable to distinguish these reported currents from leaky patch currents (ILP) in control HEK-293T cells. We suggest that NALCN functions as a sensor for the much larger UNC80/UNC79 complex, in a manner consistent with the coupling mechanism known for other weakly or non-conducting 4x6TM channel sensor proteins such as Nax or Cav1.1. We propose that NALCN serves as a variable sensor that responds to calcium or sodium ion flux, depending on whether the total cellular current density is generated more from calcium-selective or sodium-selective channels. PMID:23442378

A uniquely adaptable pore is consistent with NALCN being an ion sensor.

PubMed

Senatore, Adriano; Spafford, J David

2013-01-01

NALCN is an intriguing, orphan ion channel among the 4x6TM family of related voltage-gated cation channels, sharing a common architecture of four homologous domains consisting of six transmembrane helices, separated by three cytoplasmic linkers and delimited by N and C-terminal ends. NALCN is one of the shortest 4x6TM family members, lacking much of the variation that provides the diverse palate of gating features, and tissue specific adaptations of sodium and calcium channels. NALCN's most distinctive feature is that that it possesses a highly adaptable pore with a calcium-like EEEE selectivity filter in radially symmetrical animals and a more sodium-like EEKE or EKEE selectivity filter in bilaterally symmetrical animals including vertebrates. Two lineages of animals evolved alternative calcium-like EEEE and sodium-like EEKE / EKEE pores, spliced to regulate NALCN functions in differing cellular environments, such as muscle (heart and skeletal) and secretory tissue (brain and glands), respectively. A highly adaptable pore in an otherwise conserved ion channel in the 4x6TM channel family is not consistent with a role for NALCN in directly gating a significant ion conductance that can be either sodium ions or calcium ions. NALCN was proposed to be an expressible Gd ( 3+) -sensitive, NMDG (+) -impermeant, non-selective and ohmic leak conductance in HEK-293T cells, but we were unable to distinguish these reported currents from leaky patch currents (ILP) in control HEK-293T cells. We suggest that NALCN functions as a sensor for the much larger UNC80/UNC79 complex, in a manner consistent with the coupling mechanism known for other weakly or non-conducting 4x6TM channel sensor proteins such as Nax or Cav 1.1. We propose that NALCN serves as a variable sensor that responds to calcium or sodium ion flux, depending on whether the total cellular current density is generated more from calcium-selective or sodium-selective channels.

Tinamit: Making coupled system dynamics models accessible to stakeholders

NASA Astrophysics Data System (ADS)

Malard, Julien; Inam Baig, Azhar; Rojas Díaz, Marcela; Hassanzadeh, Elmira; Adamowski, Jan; Tuy, Héctor; Melgar-Quiñonez, Hugo

2017-04-01

Model coupling is increasingly used as a method of combining the best of two models when representing socio-environmental systems, though barriers to successful model adoption by stakeholders are particularly present with the use of coupled models, due to their high complexity and typically low implementation flexibility. Coupled system dynamics - physically-based modelling is a promising method to improve stakeholder participation in environmental modelling while retaining a high level of complexity for physical process representation, as the system dynamics components are readily understandable and can be built by stakeholders themselves. However, this method is not without limitations in practice, including 1) inflexible and complicated coupling methods, 2) difficult model maintenance after the end of the project, and 3) a wide variety of end-user cultures and languages. We have developed the open-source Python-language software tool Tinamit to overcome some of these limitations to the adoption of stakeholder-based coupled system dynamics - physically-based modelling. The software is unique in 1) its inclusion of both a graphical user interface (GUI) and a library of available commands (API) that allow users with little or no coding abilities to rapidly, effectively, and flexibly couple models, 2) its multilingual support for the GUI, allowing users to couple models in their preferred language (and to add new languages as necessary for their community work), and 3) its modular structure allowing for very easy model coupling and modification without the direct use of code, and to which programming-savvy users can easily add support for new types of physically-based models. We discuss how the use of Tinamit for model coupling can greatly increase the accessibility of coupled models to stakeholders, using an example of a stakeholder-built system dynamics model of soil salinity issues in Pakistan coupled with the physically-based soil salinity and water flow model

Dynamic Pore-Scale Imaging of Reactive Transport in Heterogeneous Carbonates at Reservior Conditions

NASA Astrophysics Data System (ADS)

Menke, Hannah; Bijeljic, Branko; Andrew, Matthew; Blunt, Martin

2014-05-01

Sequestering carbon in deep geologic formations is one way of reducing anthropogenic CO2 emissions. Carbon capture, Utilization, and Storage (CCUS) in carbonate reservoirs has the added benefit of mobilizing more oil for extraction, increasing oil reservoir yield, and generating revenue while also mitigating climate change. The magnitude, speed, and type of dissolution are dependent the intrinsic properties of the rock. Understanding how small changes in the pore structure affect dissolution is paramount for successful predictive modelling both on the pore-scale and for up-scaled reservoir simulations. We propose an experimental method whereby both 'Pink Beam' synchrotron radiation and a Micro-CT lab source are used in dynamic X-ray microtomography to investigate the pore structure changes in carbonate rocks of varying heterogeneity at high temperatures and pressures. Four carbonate rock types were studied, two relatively homogeneous carbonates, Ketton and Mt. Gambier, and two very heterogeneous carbonates, Estalliades and Portland Basebed. Each rock type was imaged under the same reservoir and flow conditions to gain insight into the impact of heterogeneity. A 4-mm carbonate core was injected with CO2-saturated brine at 10 MPa and 50oC for 2 hours. Depending on sample heterogeneity and X-ray source, tomographic images were taken at between 30-second and 20-minute time-resolutions and a 4-micron spatial resolution during injection. Changes in porosity, permeability, and structure were obtained by first binning and filtering the images, then binarizing them with watershed segmentation, and finally extracting a pore/throat network. Furthermore, pore-scale flow modelling was performed directly on the binarized image and used to track velocity distributions as the pore network evolved. Significant differences in dissolution type and magnitude were found for each rock type. The most homogeneous carbonate, Ketton, was seen to have predominately uniform dissolution with

Nitrous oxide and methane dynamics in a coral reef lagoon driven by pore water exchange: Insights from automated high-frequency observations

NASA Astrophysics Data System (ADS)

O'Reilly, Chiara; Santos, Isaac R.; Cyronak, Tyler; McMahon, Ashly; Maher, Damien T.

2015-04-01

Automated cavity ring down spectroscopy was used to make continuous measurements of dissolved methane, nitrous oxide, and carbon dioxide in a coral reef lagoon for 2 weeks (Heron Island, Great Barrier Reef). Radon (222Rn) was used to trace the influence of tidally driven pore water exchange on greenhouse gas dynamics. Clear tidal variation was observed for CH4, which correlated to 222Rn in lagoon waters. N2O correlated to 222Rn during the day only, which appears to be a response to coupled nitrification-denitrification in oxic sediments, fueled by nitrate derived from bird guano. The lagoon was a net source of CH4 and N2O to the atmosphere and a sink for atmospheric CO2. The estimated pore water-derived CH4 and N2O fluxes were 3.2-fold and 24.0-fold greater than the fluxes to the atmosphere. Overall, pore water and/or groundwater exchange were the only important sources of CH4 and major controls of N2O in the coral reef lagoon.

Proposal for quantum gates in permanently coupled antiferromagnetic spin rings without need of local fields.

PubMed

Troiani, Filippo; Affronte, Marco; Carretta, Stefano; Santini, Paolo; Amoretti, Giuseppe

2005-05-20

We propose a scheme for the implementation of quantum gates which is based on the qubit encoding in antiferromagnetic molecular rings. We show that a proper engineering of the intercluster link would result in an effective coupling that vanishes as far as the system is kept in the computational space, while it is turned on by a selective excitation of specific auxiliary states. These are also shown to allow the performing of single-qubit and two-qubit gates without an individual addressing of the rings by means of local magnetic fields.

Dynamics of water in the amphiphilic pore of amyloid β fibrils

NASA Astrophysics Data System (ADS)

GhattyVenkataKrishna, Pavan K.; Mostofian, Barmak

2013-09-01

Alzheimers disease related amyloid peptide, Aβ, forms a fibrillar structure through aggregation. The aggregate is stabilized by a salt bridge that is responsible for the formation of an amphiphilic pore that can accommodate water molecules. None of the reported structures of Aβ, however, contain water. We present results from molecular dynamics simulations on dimeric Aβ fibrils solvated in water. Water penetrates and fills the amphiphilic pore increasing its volume. We observe a thick wire of water that is translationally and rotationally stiff in comparison to bulk water and may be essential for the stabilization of the amyloid Aβ protein.

Pore-scale modeling of hydromechanical coupled mechanics in hydrofracturing process

NASA Astrophysics Data System (ADS)

Chen, Zhiqiang; Wang, Moran

2017-05-01

Hydrofracturing is an important technique in petroleum industry to stimulate well production. Yet the mechanism of induced fracture growth is still not fully understood, which results in some unsatisfactory wells even with hydrofracturing treatments. In this work we establish a more accurate numerical framework for hydromechanical coupling, where the solid deformation and fracturing are modeled by discrete element method and the fluid flow is simulated directly by lattice Boltzmann method at pore scale. After validations, hydrofracturing is simulated with consideration on the strength heterogeneity effects on fracture geometry and microfailure mechanism. A modified topological index is proposed to quantify the complexity of fracture geometry. The results show that strength heterogeneity has a significant influence on hydrofracturing. In heterogeneous samples, the fracturing behavior is crack nucleation around the tip of fracture and connection of it to the main fracture, which is usually accompanied by shear failure. However, in homogeneous ones the fracture growth is achieved by the continuous expansion of the crack, where the tensile failure often dominates. It is the fracturing behavior that makes the fracture geometry in heterogeneous samples much more complex than that in homogeneous ones. In addition, higher pore pressure leads to more shear failure events for both heterogeneous and homogeneous samples.

Extrusion of transmitter, water and ions generates forces to close fusion pore.

PubMed

Tajparast, M; Glavinović, M I

2009-05-01

During exocytosis the fusion pore opens rapidly, then dilates gradually, and may subsequently close completely, but what controls its dynamics is not well understood. In this study we focus our attention on forces acting on the pore wall, and which are generated solely by the passage of transmitter, ions and water through the open fusion pore. The transport through the charged cylindrical nano-size pore is simulated using a coupled system of Poisson-Nernst-Planck and Navier-Stokes equations and the forces that act radially on the wall of the fusion pore are then estimated. Four forces are considered: a) inertial force, b) pressure, c) viscotic force, and d) electrostatic force. The inertial and viscotic forces are small, but the electrostatic force and the pressure are typically significant. High vesicular pressure tends to open the fusion pore, but the pressure induced by the transport of charged particles (glutamate, ions), which is predominant when the pore wall charge density is high tends to close the pore. The electrostatic force, which also depends on the charge density on the pore wall, is weakly repulsive before the pore dilates, but becomes attractive and pronounced as the pore dilates. Given that the vesicular concentration of free transmitter can change rapidly due to the release, or owing to the dissociation from the gel matrix, we evaluated how much and how rapidly a change of the vesicular K(+)-glutamate(-) concentration affects the concentration of glutamate(-) and ions in the pore and how such changes alter the radial force on the wall of the fusion pore. A step-like rise of the vesicular K(+)-glutamate(-) concentration leads to a chain of events. Pore concentration (and efflux) of both K(+) and glutamate(-) rise reaching their new steady-state values in less than 100 ns. Interestingly within a similar time interval the pore concentration of Na(+) also rises, whereas that of Cl(-) diminishes, although their extra-cellular concentration does not

Probing the cooperativity of Thermoplasma acidophilum proteasome core particle gating by NMR spectroscopy

PubMed Central

Huang, Rui; Pérez, Felipe; Kay, Lewis E.

2017-01-01

The 20S proteasome core particle (20S CP) plays an integral role in cellular homeostasis by degrading proteins no longer required for function. The process is, in part, controlled via gating residues localized to the ends of the heptameric barrel-like CP structure that occlude substrate entry pores, preventing unregulated degradation of substrates that might otherwise enter the proteasome. Previously, we showed that the N-terminal residues of the α-subunits of the CP from the archaeon Thermoplasma acidophilum are arranged such that, on average, two of the seven termini are localized inside the lumen of the proteasome, thereby plugging the entry pore and functioning as a gate. However, the mechanism of gating remains unclear. Using solution NMR and a labeling procedure in which a series of mixed proteasome rings are prepared such that the percentage of gate-containing subunits is varied, we address the energetics of gating and establish whether gating is a cooperative process involving the concerted action of residues from more than a single protomer. Our results establish that the intrinsic probability of a gate entering the lumen favors the in state by close to 20-fold, that entry of each gate is noncooperative, with the number of gates that can be accommodated inside the lumen a function of the substrate entry pore size and the bulkiness of the gating residues. Insight into the origin of the high affinity for the in state is obtained from spin-relaxation experiments. More generally, our approach provides an avenue for dissecting interactions of individual protomers in homo-oligomeric complexes. PMID:29087330

Web Interface for Brownian Dynamics Simulation of Ion Transport and Its Applications to Beta-Barrel Pores

PubMed Central

Lee, Kyu Il; Jo, Sunhwan; Rui, Huan; Egwolf, Bernhard; Roux, Benoît; Pastor, Richard W.; Im, Wonpil

2011-01-01

Brownian dynamics (BD) in a suitably constructed potential of mean force is an efficient and accurate method for simulating ion transport through wide ion channels. Here, a web-based graphical user interface (GUI) is presented for grand canonical Monte Carlo (GCMC) BD simulations of channel proteins: http://www.charmm-gui.org/input/gcmcbd. The webserver is designed to help users avoid most of the technical difficulties and issues encountered in setting up and simulating complex pore systems. GCMC/BD simulation results for three proteins, the voltage dependent anion channel (VDAC), α-Hemolysin, and the protective antigen pore of the anthrax toxin (PA), are presented to illustrate system setup, input preparation, and typical output (conductance, ion density profile, ion selectivity, and ion asymmetry). Two models for the input diffusion constants for potassium and chloride ions in the pore are compared: scaling of the bulk diffusion constants by 0.5, as deduced from previous all-atom molecular dynamics simulations of VDAC; and a hydrodynamics based model (HD) of diffusion through a tube. The HD model yields excellent agreement with experimental conductances for VDAC and α-Hemolysin, while scaling bulk diffusion constants by 0.5 leads to underestimates of 10–20%. For PA, simulated ion conduction values overestimate experimental values by a factor of 1.5 to 7 (depending on His protonation state and the transmembrane potential), implying that the currently available computational model of this protein requires further structural refinement. PMID:22102176

Reversible Gating of Plasmonic Coupling for Optical Signal Amplification.

PubMed

Khoury, Christopher G; Fales, Andrew M; Vo-Dinh, Tuan

2016-07-20

Amplification of optical signals is useful for a wide variety of applications, ranging from data signal transmission to chemical sensing and biomedical diagnostics. One such application in chemical sensing is surface-enhanced Raman scattering (SERS), an important technique for increasing the Raman signal using the plasmonic effect of enhanced electromagnetic fields associated with metallic nanostructures. One of the most important limitations of SERS-based amplification is the difficulty to reproducibly control the SERS signal. Here, we describe the design and implementation of a unique hybrid system capable of producing reversible gating of plasmonic coupling for Raman signal amplification. The hybrid system is composed of two subsystems: (1) colloidal magneto-plasmonic nanoparticles for SERS enhancement and (2) a micromagnet substrate with an externally applied magnetic field to modulate the colloidal nanoparticles. For this proof of concept demonstration, the nanoparticles were labeled with a Raman-active dye, and it was shown that the detected SERS signal could be reproducibly modulated by controlling the externally applied magnetic field. The developed system provides a simple, robust, inexpensive, and reusable device for SERS signal modulation. These properties will open up new possibilities for optical signal amplification and gating as well for high-throughput, reproducible SERS detection.

Web interface for Brownian dynamics simulation of ion transport and its applications to beta-barrel pores.

PubMed

Lee, Kyu Il; Jo, Sunhwan; Rui, Huan; Egwolf, Bernhard; Roux, Benoît; Pastor, Richard W; Im, Wonpil

2012-01-30

Brownian dynamics (BD) based on accurate potential of mean force is an efficient and accurate method for simulating ion transport through wide ion channels. Here, a web-based graphical user interface (GUI) is presented for carrying out grand canonical Monte Carlo (GCMC) BD simulations of channel proteins: http://www.charmm-gui.org/input/gcmcbd. The webserver is designed to help users avoid most of the technical difficulties and issues encountered in setting up and simulating complex pore systems. GCMC/BD simulation results for three proteins, the voltage dependent anion channel (VDAC), α-Hemolysin (α-HL), and the protective antigen pore of the anthrax toxin (PA), are presented to illustrate the system setup, input preparation, and typical output (conductance, ion density profile, ion selectivity, and ion asymmetry). Two models for the input diffusion constants for potassium and chloride ions in the pore are compared: scaling of the bulk diffusion constants by 0.5, as deduced from previous all-atom molecular dynamics simulations of VDAC, and a hydrodynamics based model (HD) of diffusion through a tube. The HD model yields excellent agreement with experimental conductances for VDAC and α-HL, while scaling bulk diffusion constants by 0.5 leads to underestimates of 10-20%. For PA, simulated ion conduction values overestimate experimental values by a factor of 1.5-7 (depending on His protonation state and the transmembrane potential), implying that the currently available computational model of this protein requires further structural refinement. Copyright © 2011 Wiley Periodicals, Inc.

Gate frequency sweep: An effective method to evaluate the dynamic performance of AlGaN/GaN power heterojunction field effect transistors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Santi, C. de; Meneghini, M., E-mail: matteo.meneghini@dei.unipd.it; Meneghesso, G.

2014-08-18

With this paper we propose a test method for evaluating the dynamic performance of GaN-based transistors, namely, gate-frequency sweep measurements: the effectiveness of the method is verified by characterizing the dynamic performance of Gate Injection Transistors. We demonstrate that this method can provide an effective description of the impact of traps on the transient performance of Heterojunction Field Effect Transistors, and information on the properties (activation energy and cross section) of the related defects. Moreover, we discuss the relation between the results obtained by gate-frequency sweep measurements and those collected by conventional drain current transients and double pulse characterization.

Active Site Gate Dynamics Modulate the Catalytic Activity of the Ubiquitination Enzyme E2-25K.

PubMed

Rout, Manoj K; Lee, Brian L; Lin, Aiyang; Xiao, Wei; Spyracopoulos, Leo

2018-05-03

The ubiquitin proteasome system (UPS) signals for degradation of proteins through attachment of K48-linked polyubiquitin chains, or alterations in protein-protein recognition through attachment of K63-linked chains. Target proteins are ubiquitinated in three sequential chemical steps by a three-component enzyme system. Ubiquitination, or E2 enzymes, catalyze the central step by facilitating reaction of a target protein lysine with the C-terminus of Ub that is attached to the active site cysteine of the E2 through a thioester bond. E2 reactivity is modulated by dynamics of an active site gate, whose central residue packs against the active site cysteine in a closed conformation. Interestingly, for the E2 Ubc13, which specifically catalyzes K63-linked ubiquitination, the central gate residue adopts an open conformation. We set out to determine if active site gate dynamics play a role in catalysis for E2-25K, which adopts the canonical, closed gate conformation, and which selectively synthesizes K48-linked ubiquitin chains. Gate dynamics were characterized using mutagenesis of key residues, combined with enzyme kinetics measurements, and main chain NMR relaxation. The experimental data were interpreted with all atom MD simulations. The data indicate that active site gate opening and closing rates for E2-25K are precisely balanced.

Long-pore Electrostatics in Inward-rectifier Potassium Channels

PubMed Central

Robertson, Janice L.; Palmer, Lawrence G.; Roux, Benoît

2008-01-01

Inward-rectifier potassium (Kir) channels differ from the canonical K+ channel structure in that they possess a long extended pore (∼85 Å) for ion conduction that reaches deeply into the cytoplasm. This unique structural feature is presumably involved in regulating functional properties specific to Kir channels, such as conductance, rectification block, and ligand-dependent gating. To elucidate the underpinnings of these functional roles, we examine the electrostatics of an ion along this extended pore. Homology models are constructed based on the open-state model of KirBac1.1 for four mammalian Kir channels: Kir1.1/ROMK, Kir2.1/IRK, Kir3.1/GIRK, and Kir6.2/KATP. By solving the Poisson-Boltzmann equation, the electrostatic free energy of a K+ ion is determined along each pore, revealing that mammalian Kir channels provide a favorable environment for cations and suggesting the existence of high-density regions in the cytoplasmic domain and cavity. The contribution from the reaction field (the self-energy arising from the dielectric polarization induced by the ion's charge in the complex geometry of the pore) is unfavorable inside the long pore. However, this is well compensated by the electrostatic interaction with the static field arising from the protein charges and shielded by the dielectric surrounding. Decomposition of the static field provides a list of residues that display remarkable correspondence with existing mutagenesis data identifying amino acids that affect conduction and rectification. Many of these residues demonstrate interactions with the ion over long distances, up to 40 Å, suggesting that mutations potentially affect ion or blocker energetics over the entire pore. These results provide a foundation for understanding ion interactions in Kir channels and extend to the study of ion permeation, block, and gating in long, cation-specific pores. PMID:19001143

Tiny Pores Observed by New Solar Telescope and Hinode

NASA Astrophysics Data System (ADS)

Cho, KyungSuk; Bong, S.; Chae, J.; Kim, Y.; Park, Y.; Ahn, K.; Katsukawa, Y.

2011-05-01

Seoul National University and Korea Astronomy and Space Science Institute installed Fast Imaging Solar Spectrograph (FISS) in the Cude room of the 1.6 m New Solar Telescope (NST) at Big Bear Solar Observatory on May 14, 2010. FISS is a unique system that can do imaging of H-alpha and Ca II 8542 band simultaneously, which is quite suitable for studying of dynamics of chromosphere. To investigate the relationship between the photospheric and low-chromospheric motions at the pore region, we took a coordinate observation with NST/FISS and Hinode/SOT for new emerging active region (AR11117) on October 26, 2010. In the observed region, we could find two tiny pores and two small magnetic concentrations (SMCs), which have similar magnetic flux with the pores but do not look dark. Magnetic flux density and Doppler velocities at the photosphere are estimated by applying the center-of-gravity (COG) method to the HINODE/spectropolarimeter (SP) data. The line-of-sight motions above the photosphere are determined by adopting the bisector method to the wing spectra of Ha and CaII 8542 lines. As results, we found the followings. (1)There are upflow motion on the pores and downflow motion on the SMCs. (2)Towards the CaII 8542 line center, upflow motion decrease and turn to downward motion in pores, while the speed of down flow motion increases in the SMCs. (3)There is oscillating motion above pores and the SMCs, and this motion keep its pattern along the height. (4) As height increase, there is a general tendency of the speed shift to downward on pores and the SMCs. In this poster, we will present preliminary understanding of the coupling of pore dynamics between the photosphere and the low-chromosphere.

Direct Numerical Simulation of Low Capillary Number Pore Scale Flows

NASA Astrophysics Data System (ADS)

Esmaeilzadeh, S.; Soulaine, C.; Tchelepi, H.

2017-12-01

The arrangement of void spaces and the granular structure of a porous medium determines multiple macroscopic properties of the rock such as porosity, capillary pressure, and relative permeability. Therefore, it is important to study the microscopic structure of the reservoir pores and understand the dynamics of fluid displacements through them. One approach for doing this, is direct numerical simulation of pore-scale flow that requires a robust numerical tool for prediction of fluid dynamics and a detailed understanding of the physical processes occurring at the pore-scale. In pore scale flows with a low capillary number, Eulerian multiphase methods are well-known to produce additional vorticity close to the interface. This is mainly due to discretization errors which lead to an imbalance of capillary pressure and surface tension forces that causes unphysical spurious currents. At the pore scale, these spurious currents can become significantly stronger than the average velocity in the phases, and lead to unphysical displacement of the interface. In this work, we first investigate the capability of the algebraic Volume of Fluid (VOF) method in OpenFOAM for low capillary number pore scale flow simulations. Afterward, we compare VOF results with a Coupled Level-Set Volume of Fluid (CLSVOF) method and Iso-Advector method. It has been shown that the former one reduces the VOF's unphysical spurious currents in some cases, and both are known to capture interfaces sharper than VOF. As the conclusion, we will investigate that whether the use of CLSVOF or Iso-Advector will lead to less spurious velocities and more accurate results for capillary driven pore-scale multiphase flows or not. Keywords: Pore-scale multiphase flow, Capillary driven flows, Spurious currents, OpenFOAM

Pore invasion dynamics during fluid front displacement in porous media determine functional pore size distribution and phase entrapment

NASA Astrophysics Data System (ADS)

Moebius, F.; Or, D.

2012-12-01

Dynamics of fluid fronts in porous media shape transport properties of the unsaturated zone and affect management of petroleum reservoirs and their storage properties. What appears macroscopically as smooth and continuous motion of a displacement fluid front may involve numerous rapid interfacial jumps often resembling avalanches of invasion events. Direct observations using high-speed camera and pressure sensors in sintered glass micro-models provide new insights on the influence of flow rates, pore size, and gravity on invasion events and on burst size distribution. Fundamental differences emerge between geometrically-defined pores and "functional" pores invaded during a single burst (invasion event). The waiting times distribution of individual invasion events and decay times of inertial oscillations (following a rapid interfacial jump) are characteristics of different displacement regimes. An invasion percolation model with gradients and including the role of inertia provide a framework for linking flow regimes with invasion sequences and phase entrapment. Model results were compared with measurements and with early studies on invasion burst sizes and waiting times distribution during slow drainage processes by Måløy et al. [1992]. The study provides new insights into the discrete invasion events and their weak links with geometrically-deduced pore geometry. Results highlight factors controlling pore invasion events that exert strong influence on macroscopic phenomena such as front morphology and residual phase entrapment shaping hydraulic properties after the passage of a fluid front.

Application of a pore-scale reactive transport model to a natural analog for reaction-induced pore alterations

DOE PAGES

Yoon, Hongkyu; Major, Jonathan; Dewers, Thomas; ...

2017-01-05

Dissolved CO 2 in the subsurface resulting from geological CO 2 storage may react with minerals in fractured rocks, confined aquifers, or faults, resulting in mineral precipitation and dissolution. The overall rate of reaction can be affected by coupled processes including hydrodynamics, transport, and reactions at the (sub) pore-scale. In this work pore-scale modeling of coupled fluid flow, reactive transport, and heterogeneous reactions at the mineral surface is applied to account for permeability alterations caused by precipitation-induced pore-blocking. This paper is motivated by observations of CO 2 seeps from a natural CO 2 sequestration analog, Crystal Geyser, Utah. Observations alongmore » the surface exposure of the Little Grand Wash fault indicate the lateral migration of CO 2 seep sites (i.e., alteration zones) of 10–50 m width with spacing on the order of ~100 m over time. Sandstone permeability in alteration zones is reduced by 3–4 orders of magnitude by carbonate cementation compared to unaltered zones. One granular porous medium and one fracture network systems are used to conceptually represent permeable porous media and locations of conduits controlled by fault-segment intersections and/or topography, respectively. Simulation cases accounted for a range of reaction regimes characterized by the Damköhler (Da) and Peclet (Pe) numbers. Pore-scale simulation results demonstrate that combinations of transport (Pe), geochemical conditions (Da), solution chemistry, and pore and fracture configurations contributed to match key patterns observed in the field of how calcite precipitation alters flow paths by pore plugging. This comparison of simulation results with field observations reveals mechanistic explanations of the lateral migration and enhances our understanding of subsurface processes associated with the CO 2 injection. In addition, permeability and porosity relations are constructed from pore-scale simulations which account for a range of

Possible Dynamically Gated Conductance along Heme Wires in Bacterial Multiheme Cytochromes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smith, Dayle MA; Rosso, Kevin M.

2014-07-24

The staggered cross decaheme configuration of electron transfer co-factors in the outer-membrane cytochrome MtrF may serve as a prototype for conformationally-gated multi-heme electron transport. Derived from the bacterium Shewanella oneidensis, the staggered cross configuration reveals intersecting c-type octaheme and tetraheme “wires” containing thermodynamic “hills” and “valleys”, suggesting that the protein structure may include a dynamical mechanism for conductance and pathway switching depending on enzymatic functional need. Recent molecular simulations have established the pair-wise electronic couplings, redox potentials, and reorganization energies to predict the maximum conductance along the various heme wire pathways by sequential hopping of a single electron (PNAS (2014)more » 11,611-616). Here, we expand this information with classical molecular and statistical mechanics calculations of large-amplitude protein dynamics in MtrF, to address its potential to modulate pathway conductance, including assessment of the effect of the total charge state. Explicit solvent molecular dynamics simulations of fully oxidized and fully reduced MtrF employing ten independent 50-ns simulations at 300 K and 1 atm showed that reduced MtrF is more expanded and explores more conformational space than oxidized MtrF, and that heme reduction leads to increased heme solvent exposure. The slowest mode of collective decaheme motion is 90% similar between the oxidized and reduced states, and consists primarily of inter-heme separation with minor rotational contributions. The frequency of this motion is 1.7×107 s 1 for fully-oxidized and fully-reduced MtrF, respectively, slower than the downhill electron transfer rates between stacked heme pairs at the octaheme termini and faster than the electron transfer rates between parallel hemes in the tetraheme chain. This implies that MtrF uses slow conformational fluctuations to modulate electron flow along the octaheme

A thermodynamic approach to alamethicin pore formation.

PubMed

Rahaman, Asif; Lazaridis, Themis

2014-01-01

The structure and energetics of alamethicin Rf30 monomer to nonamer in cylindrical pores of 5 to 11Å radius are investigated using molecular dynamics simulations in an implicit membrane model that includes the free energy cost of acyl chain hydrophobic area exposure. Stable, low energy pores are obtained for certain combinations of radius and oligomeric number. The trimer and the tetramer formed 6Å pores that appear closed while the larger oligomers formed open pores at their optimal radius. The hexamer in an 8Å pore and the octamer in an 11Å pore give the lowest effective energy per monomer. However, all oligomers beyond the pentamer have comparable energies, consistent with the observation of multiple conductance levels. The results are consistent with the widely accepted "barrel-stave" model. The N terminal portion of the molecule exhibits smaller tilt with respect to the membrane normal than the C terminal portion, resulting in a pore shape that is a hybrid between a funnel and an hourglass. Transmembrane voltage has little effect on the structure of the oligomers but enhances or decreases their stability depending on its orientation. Antiparallel bundles are lower in energy than the commonly accepted parallel ones and could be present under certain experimental conditions. Dry aggregates (without an aqueous pore) have lower average effective energy than the corresponding aggregates in a pore, suggesting that alamethicin pores may be excited states that are stabilized in part by voltage and in part by the ion flow itself. © 2013.

Characterization of a gated fiber-optic-coupled detector for application in clinical electron beam dosimetry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tanyi, James A.; Nitzling, Kevin D.; Lodwick, Camille J.

2011-02-15

Purpose: Assessment of the fundamental dosimetric characteristics of a novel gated fiber-optic-coupled dosimetry system for clinical electron beam irradiation. Methods: The response of fiber-optic-coupled dosimetry system to clinical electron beam, with nominal energy range of 6-20 MeV, was evaluated for reproducibility, linearity, and output dependence on dose rate, dose per pulse, energy, and field size. The validity of the detector system's response was assessed in correspondence with a reference ionization chamber. Results: The fiber-optic-coupled dosimetry system showed little dependence to dose rate variations (coefficient of variation {+-}0.37%) and dose per pulse changes (with 0.54% of reference chamber measurements). The reproducibilitymore » of the system was {+-}0.55% for dose fractions of {approx}100 cGy. Energy dependence was within {+-}1.67% relative to the reference ionization chamber for the 6-20 MeV nominal electron beam energy range. The system exhibited excellent linear response (R{sup 2}=1.000) compared to reference ionization chamber in the dose range of 1-1000 cGy. The output factors were within {+-}0.54% of the corresponding reference ionization chamber measurements. Conclusions: The dosimetric properties of the gated fiber-optic-coupled dosimetry system compare favorably to the corresponding reference ionization chamber measurements and show considerable potential for applications in clinical electron beam radiotherapy.« less

Retinal Cyclic Nucleotide-Gated Channels: From Pathophysiology to Therapy.

PubMed

Michalakis, Stylianos; Becirovic, Elvir; Biel, Martin

2018-03-07

The first step in vision is the absorption of photons by the photopigments in cone and rod photoreceptors. After initial amplification within the phototransduction cascade the signal is translated into an electrical signal by the action of cyclic nucleotide-gated (CNG) channels. CNG channels are ligand-gated ion channels that are activated by the binding of cyclic guanosine monophosphate (cGMP) or cyclic adenosine monophosphate (cAMP). Retinal CNG channels transduce changes in intracellular concentrations of cGMP into changes of the membrane potential and the Ca 2+ concentration. Structurally, the CNG channels belong to the superfamily of pore-loop cation channels and share a common gross structure with hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and voltage-gated potassium channels (KCN). In this review, we provide an overview on the molecular properties of CNG channels and describe their physiological role in the phototransduction pathways. We also discuss insights into the pathophysiological role of CNG channel proteins that have emerged from the analysis of CNG channel-deficient animal models and human CNG channelopathies. Finally, we summarize recent gene therapy activities and provide an outlook for future clinical application.

Retinal Cyclic Nucleotide-Gated Channels: From Pathophysiology to Therapy

PubMed Central

Biel, Martin

2018-01-01

The first step in vision is the absorption of photons by the photopigments in cone and rod photoreceptors. After initial amplification within the phototransduction cascade the signal is translated into an electrical signal by the action of cyclic nucleotide-gated (CNG) channels. CNG channels are ligand-gated ion channels that are activated by the binding of cyclic guanosine monophosphate (cGMP) or cyclic adenosine monophosphate (cAMP). Retinal CNG channels transduce changes in intracellular concentrations of cGMP into changes of the membrane potential and the Ca2+ concentration. Structurally, the CNG channels belong to the superfamily of pore-loop cation channels and share a common gross structure with hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and voltage-gated potassium channels (KCN). In this review, we provide an overview on the molecular properties of CNG channels and describe their physiological role in the phototransduction pathways. We also discuss insights into the pathophysiological role of CNG channel proteins that have emerged from the analysis of CNG channel-deficient animal models and human CNG channelopathies. Finally, we summarize recent gene therapy activities and provide an outlook for future clinical application. PMID:29518895

Single-electron thermal devices coupled to a mesoscopic gate

NASA Astrophysics Data System (ADS)

Sánchez, Rafael; Thierschmann, Holger; Molenkamp, Laurens W.

2017-11-01

We theoretically investigate the propagation of heat currents in a three-terminal quantum dot engine. Electron-electron interactions introduce state-dependent processes which can be resolved by energy-dependent tunneling rates. We identify the relevant transitions which define the operation of the system as a thermal transistor or a thermal diode. In the former case, thermal-induced charge fluctuations in the gate dot modify the thermal currents in the conductor with suppressed heat injection, resulting in huge amplification factors and the possible gating with arbitrarily low energy cost. In the latter case, enhanced correlations of the state-selective tunneling transitions redistribute heat flows giving high rectification coefficients and the unexpected cooling of one conductor terminal by heating the other one. We propose quantum dot arrays as a possible way to achieve the extreme tunneling asymmetries required for the different operations.

Multiple Approaches to Characterizing Nano-Pore Structure of Barnett Shale

NASA Astrophysics Data System (ADS)

Hu, Q.; Gao, Z.; Ewing, R. P.; Dultz, S.; Kaufmann, J.; Hamamoto, S.; Webber, B.; Ding, M.

2013-12-01

Microscopic characteristics of porous media - pore shape, pore-size distribution, and pore connectivity - control fluid flow and mass transport. This presentation discusses various approaches to investigating nano-pore structure of Barnett shale, with its implications in gas production behavior. The innovative approaches include imbibition, tracer diffusion, edge-accessible porosity, porosimetry (mercury intrusion porosimetry, nitrogen and water vapor sorption isotherms, and nuclear magnetic resonance cyroporometry), and imaging (Wood's metal impregnation followed with laser ablation-inductively coupled plasma-mass spectrometry, focused ion beam/scanning electron microscopy, and small angle neutron scattering). Results show that the shale pores are predominantly in the nm size range, with measured median pore-throat diameters about 5 nm. But small pore size is not the major contributor to low gas recovery; rather, the low mass diffusivity appears to be caused by low pore connectivity of Barnett shale. Chemical diffusion in sparsely-connected pore spaces is not well described by classical Fickian behavior; anomalous behavior is suggested by percolation theory, and confirmed by results of imbibition and diffusion tests. Our evolving complementary approaches, with their several advantages and disadvantages, provide a rich toolbox for tackling the nano-pore structure characteristics of shales and other natural rocks.

Deterministic quantum controlled-PHASE gates based on non-Markovian environments

NASA Astrophysics Data System (ADS)

Zhang, Rui; Chen, Tian; Wang, Xiang-Bin

2017-12-01

We study the realization of the quantum controlled-PHASE gate in an atom-cavity system beyond the Markovian approximation. The general description of the dynamics for the atom-cavity system without any approximation is presented. When the spectral density of the reservoir has the Lorentz form, by making use of the memory backflow from the reservoir, we can always construct the deterministic quantum controlled-PHASE gate between a photon and an atom, no matter the atom-cavity coupling strength is weak or strong. While, the phase shift in the output pulse hinders the implementation of quantum controlled-PHASE gates in the sub-Ohmic, Ohmic or super-Ohmic reservoirs.

Non-scaling behavior of electroosmotic flow in voltage-gated nanopores

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lian, Cheng; Gallegos, Alejandro; Liu, Honglai

2017-01-01

Ionic size effects and electrostatic correlations result in the non-monotonic dependence of the electrical conductivity on the pore size. For ion transport at a high gating voltage, the conductivity oscillates with the pore size due to a significant overlap of the electric double layers.

Identification of an evolutionarily conserved extracellular threonine residue critical for surface expression and its potential coupling of adjacent voltage-sensing and gating domains in voltage-gated potassium channels.

PubMed

Mckeown, Lynn; Burnham, Matthew P; Hodson, Charlotte; Jones, Owen T

2008-10-31

The dynamic expression of voltage-gated potassium channels (Kvs) at the cell surface is a fundamental factor controlling membrane excitability. In exploring possible mechanisms controlling Kv surface expression, we identified a region in the extracellular linker between the first and second of the six (S1-S6) transmembrane-spanning domains of the Kv1.4 channel, which we hypothesized to be critical for its biogenesis. Using immunofluorescence microscopy, flow cytometry, patch clamp electrophysiology, and mutagenesis, we identified a single threonine residue at position 330 within the Kv1.4 S1-S2 linker that is absolutely required for cell surface expression. Mutation of Thr-330 to an alanine, aspartate, or lysine prevented surface expression. However, surface expression occurred upon co-expression of mutant and wild type Kv1.4 subunits or mutation of Thr-330 to a serine. Mutation of the corresponding residue (Thr-211) in Kv3.1 to alanine also caused intracellular retention, suggesting that the conserved threonine plays a generalized role in surface expression. In support of this idea, sequence comparisons showed conservation of the critical threonine in all Kv families and in organisms across the evolutionary spectrum. Based upon the Kv1.2 crystal structure, further mutagenesis, and the partial restoration of surface expression in an electrostatic T330K bridging mutant, we suggest that Thr-330 hydrogen bonds to equally conserved outer pore residues, which may include a glutamate at position 502 that is also critical for surface expression. We propose that Thr-330 serves to interlock the voltage-sensing and gating domains of adjacent monomers, thereby yielding a structure competent for the surface expression of functional tetramers.

Beyond voltage-gated ion channels: Voltage-operated membrane proteins and cellular processes.

PubMed

Zhang, Jianping; Chen, Xingjuan; Xue, Yucong; Gamper, Nikita; Zhang, Xuan

2018-04-18

Voltage-gated ion channels were believed to be the only voltage-sensitive proteins in excitable (and some non-excitable) cells for a long time. Emerging evidence indicates that the voltage-operated model is shared by some other transmembrane proteins expressed in both excitable and non-excitable cells. In this review, we summarize current knowledge about voltage-operated proteins, which are not classic voltage-gated ion channels as well as the voltage-dependent processes in cells for which single voltage-sensitive proteins have yet to be identified. Particularly, we will focus on the following. (1) Voltage-sensitive phosphoinositide phosphatases (VSP) with four transmembrane segments homologous to the voltage sensor domain (VSD) of voltage-gated ion channels; VSPs are the first family of proteins, other than the voltage-gated ion channels, for which there is sufficient evidence for the existence of the VSD domain; (2) Voltage-gated proton channels comprising of a single voltage-sensing domain and lacking an identified pore domain; (3) G protein coupled receptors (GPCRs) that mediate the depolarization-evoked potentiation of Ca 2+ mobilization; (4) Plasma membrane (PM) depolarization-induced but Ca 2+ -independent exocytosis in neurons. (5) Voltage-dependent metabolism of phosphatidylinositol 4,5-bisphosphate (PtdIns[4,5]P 2 , PIP 2 ) in the PM. These recent discoveries expand our understanding of voltage-operated processes within cellular membranes. © 2018 Wiley Periodicals, Inc.

Active pixel sensor pixel having a photodetector whose output is coupled to an output transistor gate

NASA Technical Reports Server (NTRS)

Fossum, Eric R. (Inventor); Nakamura, Junichi (Inventor); Kemeny, Sabrina E. (Inventor)

2005-01-01

An imaging device formed as a monolithic complementary metal oxide semiconductor integrated circuit in an industry standard complementary metal oxide semiconductor process, the integrated circuit including a focal plane array of pixel cells, each one of the cells including a photogate overlying the substrate for accumulating photo-generated charge in an underlying portion of the substrate and a charge coupled device section formed on the substrate adjacent the photogate having a sensing node and at least one charge coupled device stage for transferring charge from the underlying portion of the substrate to the sensing node. There is also a readout circuit, part of which can be disposed at the bottom of each column of cells and be common to all the cells in the column. A Simple Floating Gate (SFG) pixel structure could also be employed in the imager to provide a non-destructive readout and smaller pixel sizes.

Ion Transport through Membrane-Spanning Nanopores Studied by Molecular Dynamics Simulations and Continuum Electrostatics Calculations

PubMed Central

Peter, Christine; Hummer, Gerhard

2005-01-01

Narrow hydrophobic regions are a common feature of biological channels, with possible roles in ion-channel gating. We study the principles that govern ion transport through narrow hydrophobic membrane pores by molecular dynamics simulation of model membranes formed of hexagonally packed carbon nanotubes. We focus on the factors that determine the energetics of ion translocation through such nonpolar nanopores and compare the resulting free-energy barriers for pores with different diameters corresponding to the gating regions in closed and open forms of potassium channels. Our model system also allows us to compare the results from molecular dynamics simulations directly to continuum electrostatics calculations. Both simulations and continuum calculations show that subnanometer wide pores pose a huge free-energy barrier for ions, but a small increase in the pore diameter to ∼1 nm nearly eliminates that barrier. We also find that in those wider channels the ion mobility is comparable to that in the bulk phase. By calculating local electrostatic potentials, we show that the long range Coulomb interactions of ions are strongly screened in the wide water-filled channels. Whereas continuum calculations capture the overall energetics reasonably well, the local water structure, which is not accounted for in this model, leads to interesting effects such as the preference of hydrated ions to move along the pore wall rather than through the center of the pore. PMID:16006629

Multiple receptors coupled to phospholipase C gate long-term depression in visual cortex.

PubMed

Choi, Se-Young; Chang, Jeff; Jiang, Bin; Seol, Geun-Hee; Min, Sun-Seek; Han, Jung-Soo; Shin, Hee-Sup; Gallagher, Michela; Kirkwood, Alfredo

2005-12-07

Long-term depression (LTD) in sensory cortices depends on the activation of NMDA receptors. Here, we report that in visual cortical slices, the induction of LTD (but not long-term potentiation) also requires the activation of receptors coupled to the phospholipase C (PLC) pathway. Using immunolesions in combination with agonists and antagonists, we selectively manipulated the activation of alpha1 adrenergic, M1 muscarinic, and mGluR5 glutamatergic receptors. Inactivation of these PLC-coupled receptors prevents the induction of LTD, but only when the three receptors were inactivated together. LTD is fully restored by activating any one of them or by supplying intracellular D-myo-inositol-1,4,5-triphosphate (IP3). LTD was also impaired by intracellular application of PLC or IP3 receptor blockers, and it was absent in mice lacking PLCbeta1, the predominant PLC isoform in the forebrain. We propose that visual cortical LTD requires a minimum of PLC activity that can be supplied independently by at least three neurotransmitter systems. This essential requirement places PLC-linked receptors in a unique position to control the induction of LTD and provides a mechanism for gating visual cortical plasticity via extra-retinal inputs in the intact organism.

Side chain flexibility and the pore dimensions in the GABAA receptor

NASA Astrophysics Data System (ADS)

Rossokhin, Alexey V.; Zhorov, Boris S.

2016-07-01

Permeation of ions through open channels and their accessibility to pore-targeting drugs depend on the pore cross-sectional dimensions, which are known only for static X-ray and cryo-EM structures. Here, we have built homology models of the closed, open and desensitized α1β2γ2 GABAA receptor (GABAAR). The models are based, respectively, on the X-ray structure of α3 glycine receptor (α3 GlyR), cryo-EM structure of α1 GlyR and X-ray structure of β3 GABAAR. We employed Monte Carlo energy minimizations to explore how the pore lumen may increase due to repulsions of flexible side chains from a variable-diameter electroneutral atom (an expanding sphere) pulled through the pore. The expanding sphere computations predicted that the pore diameter averaged along the permeation pathway is larger by approximately 3 Å than that computed for the models with fixed sidechains. Our models predict three major pore constrictions located at the levels of -2', 9' and 20' residues. Residues around the -2' and 9' rings are known to form the desensitization and activation gates of GABAAR. Our computations predict that the 20' ring may also serve as GABAAR gate whose physiological role is unclear. The side chain flexibility of residues -2', 9' and 20' and hence the dimensions of the constrictions depend on the GABAAR functional state.

Domain-domain interactions determine the gating, permeation, pharmacology, and subunit modulation of the IKs ion channel.

PubMed

Zaydman, Mark A; Kasimova, Marina A; McFarland, Kelli; Beller, Zachary; Hou, Panpan; Kinser, Holly E; Liang, Hongwu; Zhang, Guohui; Shi, Jingyi; Tarek, Mounir; Cui, Jianmin

2014-12-23

Voltage-gated ion channels generate electrical currents that control muscle contraction, encode neuronal information, and trigger hormonal release. Tissue-specific expression of accessory (β) subunits causes these channels to generate currents with distinct properties. In the heart, KCNQ1 voltage-gated potassium channels coassemble with KCNE1 β-subunits to generate the IKs current (Barhanin et al., 1996; Sanguinetti et al., 1996), an important current for maintenance of stable heart rhythms. KCNE1 significantly modulates the gating, permeation, and pharmacology of KCNQ1 (Wrobel et al., 2012; Sun et al., 2012; Abbott, 2014). These changes are essential for the physiological role of IKs (Silva and Rudy, 2005); however, after 18 years of study, no coherent mechanism explaining how KCNE1 affects KCNQ1 has emerged. Here we provide evidence of such a mechanism, whereby, KCNE1 alters the state-dependent interactions that functionally couple the voltage-sensing domains (VSDs) to the pore.

Domain–domain interactions determine the gating, permeation, pharmacology, and subunit modulation of the IKs ion channel

PubMed Central

Zaydman, Mark A; Kasimova, Marina A; McFarland, Kelli; Beller, Zachary; Hou, Panpan; Kinser, Holly E; Liang, Hongwu; Zhang, Guohui; Shi, Jingyi; Tarek, Mounir; Cui, Jianmin

2014-01-01

Voltage-gated ion channels generate electrical currents that control muscle contraction, encode neuronal information, and trigger hormonal release. Tissue-specific expression of accessory (β) subunits causes these channels to generate currents with distinct properties. In the heart, KCNQ1 voltage-gated potassium channels coassemble with KCNE1 β-subunits to generate the IKs current (Barhanin et al., 1996; Sanguinetti et al., 1996), an important current for maintenance of stable heart rhythms. KCNE1 significantly modulates the gating, permeation, and pharmacology of KCNQ1 (Wrobel et al., 2012; Sun et al., 2012; Abbott, 2014). These changes are essential for the physiological role of IKs (Silva and Rudy, 2005); however, after 18 years of study, no coherent mechanism explaining how KCNE1 affects KCNQ1 has emerged. Here we provide evidence of such a mechanism, whereby, KCNE1 alters the state-dependent interactions that functionally couple the voltage-sensing domains (VSDs) to the pore. DOI: http://dx.doi.org/10.7554/eLife.03606.001 PMID:25535795

Density-dependent changes of the pore properties of the P2X2 receptor channel

PubMed Central

Fujiwara, Yuichiro; Kubo, Yoshihiro

2004-01-01

Ligand-gated ion channels underlie and play important roles in synaptic transmission, and it is generally accepted that the ion channel pores have a rigid structure that enables strict regulation of ion permeation. One exception is the P2X ATP-gated channel. After application of ATP, the ion selectivity of the P2X2 channel time-dependently changes, i.e. permeability to large cations gradually increases, and there is significant cell-to-cell variation in the intensity of inward rectification. Here we show P2X2 channel properties are correlated with the expression level: increasing P2X2 expression level in oocytes increases permeability to large cations, decreases inward rectification and increases ligand sensitivity. We also observed that the inward rectification changed in a dose-dependent manner, i.e. when low concentration of ATP was applied to an oocyte with a high expression level, the intensity of inward rectification of the evoked current was weak. Taken together, these results show that the pore properties of P2X2 channel are not static but change dynamically depending on the open channel density. Furthermore, we identified by mutagenesis study that Ile328 located at the outer mouth of the pore is critical for the density-dependent changes of P2X2. Our findings suggest synaptic transmission can be modulated by the local density-dependent changes of channel properties caused, for example, by the presence of clustering molecules. PMID:15107474

Crystal structures of a pentameric ion channel gated by alkaline pH show a widely open pore and identify a cavity for modulation.

PubMed

Hu, Haidai; Nemecz, Ákos; Van Renterghem, Catherine; Fourati, Zaineb; Sauguet, Ludovic; Corringer, Pierre-Jean; Delarue, Marc

2018-04-24

Pentameric ligand-gated ion channels (pLGICs) constitute a widespread class of ion channels, present in archaea, bacteria, and eukaryotes. Upon binding of their agonists in the extracellular domain, the transmembrane pore opens, allowing ions to go through, via a gating mechanism that can be modulated by a number of drugs. Even though high-resolution structural information on pLGICs has increased in a spectacular way in recent years, both in bacterial and in eukaryotic systems, the structure of the open channel conformation of some intensively studied receptors whose structures are known in a nonactive (closed) form, such as Erwinia chrysanthemi pLGIC (ELIC), is still lacking. Here we describe a gammaproteobacterial pLGIC from an endo-symbiont of Tevnia jerichonana (sTeLIC), whose sequence is closely related to the pLGIC from ELIC with 28% identity. We provide an X-ray crystallographic structure at 2.3 Å in an active conformation, where the pore is found to be more open than any current conformation found for pLGICs. In addition, two charged restriction rings are present in the vestibule. Functional characterization shows sTeLIC to be a cationic channel activated at alkaline pH. It is inhibited by divalent cations, but not by quaternary ammonium ions, such as tetramethylammonium. Additionally, we found that sTeLIC is allosterically potentiated by aromatic amino acids Phe and Trp, as well as their derivatives, such as 4-bromo-cinnamate, whose cocrystal structure reveals a vestibular binding site equivalent to, but more deeply buried than, the one already described for benzodiazepines in ELIC.

Structural refinement of the hERG1 pore and voltage-sensing domains with ROSETTA-membrane and molecular dynamics simulations.

PubMed

Subbotina, Julia; Yarov-Yarovoy, Vladimir; Lees-Miller, James; Durdagi, Serdar; Guo, Jiqing; Duff, Henry J; Noskov, Sergei Yu

2010-11-01

The hERG1 gene (Kv11.1) encodes a voltage-gated potassium channel. Mutations in this gene lead to one form of the Long QT Syndrome (LQTS) in humans. Promiscuous binding of drugs to hERG1 is known to alter the structure/function of the channel leading to an acquired form of the LQTS. Expectably, creation and validation of reliable 3D model of the channel have been a key target in molecular cardiology and pharmacology for the last decade. Although many models were built, they all were limited to pore domain. In this work, a full model of the hERG1 channel is developed which includes all transmembrane segments. We tested a template-driven de-novo design with ROSETTA-membrane modeling using side-chain placements optimized by subsequent molecular dynamics (MD) simulations. Although backbone templates for the homology modeled parts of the pore and voltage sensors were based on the available structures of KvAP, Kv1.2 and Kv1.2-Kv2.1 chimera channels, the missing parts are modeled de-novo. The impact of several alignments on the structure of the S4 helix in the voltage-sensing domain was also tested. Herein, final models are evaluated for consistency to the reported structural elements discovered mainly on the basis of mutagenesis and electrophysiology. These structural elements include salt bridges and close contacts in the voltage-sensor domain; and the topology of the extracellular S5-pore linker compared with that established by toxin foot-printing and nuclear magnetic resonance studies. Implications of the refined hERG1 model to binding of blockers and channels activators (potent new ligands for channel activations) are discussed. © 2010 Wiley-Liss, Inc.

A mechanism for acetylcholine receptor gating based on structure, coupling, phi, and flip.

PubMed

Gupta, Shaweta; Chakraborty, Srirupa; Vij, Ridhima; Auerbach, Anthony

2017-01-01

Nicotinic acetylcholine receptors are allosteric proteins that generate membrane currents by isomerizing ("gating") between resting and active conformations under the influence of neurotransmitters. Here, to explore the mechanisms that link the transmitter-binding sites (TBSs) with the distant gate, we use mutant cycle analyses to measure coupling between residue pairs, phi value analyses to sequence domain rearrangements, and current simulations to reproduce a microsecond shut component ("flip") apparent in single-channel recordings. Significant interactions between amino acids separated by >15 Å are rare; an exception is between the αM2-M3 linkers and the TBSs that are ∼30 Å apart. Linker residues also make significant, local interactions within and between subunits. Phi value analyses indicate that without agonists, the linker is the first region in the protein to reach the gating transition state. Together, the phi pattern and flip component suggest that a complete, resting↔active allosteric transition involves passage through four brief intermediate states, with brief shut events arising from sojourns in all or a subset. We derive energy landscapes for gating with and without agonists, and propose a structure-based model in which resting→active starts with spontaneous rearrangements of the M2-M3 linkers and TBSs. These conformational changes stabilize a twisted extracellular domain to promote transmembrane helix tilting, gate dilation, and the formation of a "bubble" that collapses to initiate ion conduction. The energy landscapes suggest that twisting is the most energetically unfavorable step in the resting→active conformational change and that the rate-limiting step in the reverse process is bubble formation. © 2017 Gupta et al.

Optimal diabatic dynamics of Majorana-based quantum gates

NASA Astrophysics Data System (ADS)

Rahmani, Armin; Seradjeh, Babak; Franz, Marcel

2017-08-01

In topological quantum computing, unitary operations on qubits are performed by adiabatic braiding of non-Abelian quasiparticles, such as Majorana zero modes, and are protected from local environmental perturbations. In the adiabatic regime, with timescales set by the inverse gap of the system, the errors can be made arbitrarily small by performing the process more slowly. To enhance the performance of quantum information processing with Majorana zero modes, we apply the theory of optimal control to the diabatic dynamics of Majorana-based qubits. While we sacrifice complete topological protection, we impose constraints on the optimal protocol to take advantage of the nonlocal nature of topological information and increase the robustness of our gates. By using the Pontryagin's maximum principle, we show that robust equivalent gates to perfect adiabatic braiding can be implemented in finite times through optimal pulses. In our implementation, modifications to the device Hamiltonian are avoided. Focusing on thermally isolated systems, we study the effects of calibration errors and external white and 1 /f (pink) noise on Majorana-based gates. While a noise-induced antiadiabatic behavior, where a slower process creates more diabatic excitations, prohibits indefinite enhancement of the robustness of the adiabatic scheme, our fast optimal protocols exhibit remarkable stability to noise and have the potential to significantly enhance the practical performance of Majorana-based information processing.

Discrete-state representation of ion permeation coupled to fast gating in a model of ClC chloride channels: comparison to multi-ion continuous space Brownian dynamics simulations.

PubMed

Coalson, Rob D; Cheng, Mary Hongying

2010-01-28

A discrete-state model of chloride ion motion in a ClC chloride channel is constructed, following a previously developed multi-ion continuous space model of the same system (Cheng, M. H.; Mamonov, A. B.; Dukes, J. W.; Coalson, R. D. J. Phys. Chem. B 2007, 111, 5956) that included a simplistic representation of the fast gate in this channel. The reducibility of the many-body continuous space to the eight discrete-state model considered in the present work is examined in detail by performing three-dimensional Brownian dynamics simulations of each allowed state-to-state transition in order to extract the appropriate rate constant for this process, and then inserting the pairwise rate constants thereby obtained into an appropriate set of kinetic master equations. Experimental properties of interest, including the rate of Cl(-) ion permeation through the open channel and the average rate of closing of the fast gate as a function of bulk Cl(-) ion concentrations in the intracellular and extracellular electrolyte reservoirs are computed. Good agreement is found between the results obtained via the eight discrete-state model versus the multi-ion continuous space model, thereby encouraging continued development of the discrete-state model to include more complex behaviors observed experimentally in these channels.

P-channel differential multiple-time programmable memory cells by laterally coupled floating metal gate fin field-effect transistors

NASA Astrophysics Data System (ADS)

Wang, Tai-Min; Chien, Wei-Yu; Hsu, Chia-Ling; Lin, Chrong Jung; King, Ya-Chin

2018-04-01

In this paper, we present a new differential p-channel multiple-time programmable (MTP) memory cell that is fully compatible with advanced 16 nm CMOS fin field-effect transistors (FinFET) logic processes. This differential MTP cell stores complementary data in floating gates coupled by a slot contact structure, which make different read currents possible on a single cell. In nanoscale CMOS FinFET logic processes, the gate dielectric layer becomes too thin to retain charges inside floating gates for nonvolatile data storage. By using a differential architecture, the sensing window of the cell can be extended and maintained by an advanced blanket boost scheme. The charge retention problem in floating gate cells can be improved by periodic restoring lost charges when significant read window narrowing occurs. In addition to high programming efficiency, this p-channel MTP cells also exhibit good cycling endurance as well as disturbance immunity. The blanket boost scheme can remedy the charge loss problem under thin gate dielectrics.

Vortices and gate-tunable bound states in a topological insulator coupled to superconducting leads

NASA Astrophysics Data System (ADS)

Finck, Aaron; Kurter, C.; Hor, Y. S.; van Harlingen, D. J.

2014-03-01

It has been predicted that zero energy Majorana bound states can be found in the core of vortices within topological superconductors. Here, we report on Andreev spectroscopy measurements of the topological insulator Bi2Se3 with a normal metal lead and one or more niobium leads. The niobium induces superconductivity in the Bi2Se3 through the proximity effect, leading to both signatures of Andreev reflection and a prominent re-entrant resistance effect. When a large magnetic field is applied perpendicular to the surface of the Bi2Se3, we observe multiple abrupt changes in the subgap conductance that are accompanied by sharp peaks in the dynamical resistance. These peaks are very sensitive to changes in magnetic field and disappear at temperatures associated with the critical temperature of the induced superconductivity. The appearance of the transitions and peaks can be tuned by a top gate. At high magnetic fields, we also find evidence of gate-tunable states, which can lead to stable zero-bias conductance peaks. We interpret our results in terms of a transition occurring within the proximity effect region of the topological insulator, likely due to the formation of vortices. We acknowledge support from Microsoft Project Q.

Coupling Oxygen Consumption with Hydrocarbon Oxidation in Bacterial Multicomponent Monooxygenases.

PubMed

Wang, Weixue; Liang, Alexandria D; Lippard, Stephen J

2015-09-15

A fundamental goal in catalysis is the coupling of multiple reactions to yield a desired product. Enzymes have evolved elegant approaches to address this grand challenge. A salient example is the biological conversion of methane to methanol catalyzed by soluble methane monooxygenase (sMMO), a member of the bacterial multicomponent monooxygenase (BMM) superfamily. sMMO is a dynamic protein complex of three components: a hydroxylase, a reductase, and a regulatory protein. The active site, a carboxylate-rich non-heme diiron center, is buried inside the 251 kDa hydroxylase component. The enzyme processes four substrates: O2, protons, electrons, and methane. To couple O2 activation to methane oxidation, timely control of substrate access to the active site is critical. Recent studies of sMMO, as well as its homologues in the BMM superfamily, have begun to unravel the mechanism. The emerging and unifying picture reveals that each substrate gains access to the active site along a specific pathway through the hydroxylase. Electrons and protons are delivered via a three-amino-acid pore located adjacent to the diiron center; O2 migrates via a series of hydrophobic cavities; and hydrocarbon substrates reach the active site through a channel or linked set of cavities. The gating of these pathways mediates entry of each substrate to the diiron active site in a timed sequence and is coordinated by dynamic interactions with the other component proteins. The result is coupling of dioxygen consumption with hydrocarbon oxidation, avoiding unproductive oxidation of the reductant rather than the desired hydrocarbon. To initiate catalysis, the reductase delivers two electrons to the diiron(III) center by binding over the pore of the hydroxylase. The regulatory component then displaces the reductase, docking onto the same surface of the hydroxylase. Formation of the hydroxylase-regulatory component complex (i) induces conformational changes of pore residues that may bring protons to the

Modal Analysis of a Steel Radial Gate Exposed to Different Water Levels

NASA Astrophysics Data System (ADS)

Brusewicz, Krzysztof; Sterpejkowicz-Wersocki, Witold; Jankowski, Robert

2017-06-01

With the increase in water retention needs and planned river regulation, it might be important to investigate the dynamic resistance of vulnerable elements of hydroelectric power plants, including steelwater locks. The most frequent dynamic loads affecting hydroengineering structures in Poland include vibrations caused by heavy road and railway traffic, piling works and mining tremors. More destructive dynamic loads, including earthquakes, may also occur in our country, although their incidence is relatively low. However, given the unpredictable nature of such events, as well as serious consequences they might cause, the study of the seismic resistance of the steel water gate, as one of the most vulnerable elements of a hydroelectric power plant, seems to be important. In this study, a steel radial gate has been analyzed. As far as water gates are concerned, it is among the most popular solutions because of its relatively small weight, compared to plain gates. A modal analysis of the steel radial gate was conducted with the use of the FEM in the ABAQUS software. All structural members were modelled using shell elements with detailed geometry representing a real structure.Water was modelled as an added mass affecting the structure. Different water levels were used to determine the most vulnerable state of the working steel water gate. The results of the modal analysis allowed us to compare the frequencies and their eigenmodes in response to different loads, which is one of the first steps in researching the dynamic properties of steel water gates and their behaviour during extreme dynamic loads, including earthquakes.

Many-body strategies for multiqubit gates: Quantum control through Krawtchouk-chain dynamics

NASA Astrophysics Data System (ADS)

Groenland, Koen; Schoutens, Kareljan

2018-04-01

We propose a strategy for engineering multiqubit quantum gates. As a first step, it employs an eigengate to map states in the computational basis to eigenstates of a suitable many-body Hamiltonian. The second step employs resonant driving to enforce a transition between a single pair of eigenstates, leaving all others unchanged. The procedure is completed by mapping back to the computational basis. We demonstrate the strategy for the case of a linear array with an even number N of qubits, with specific X X +Y Y couplings between nearest neighbors. For this so-called Krawtchouk chain, a two-body driving term leads to the iSWAPN gate, which we numerically test for N =4 and 6.

The Sensorless Pore Module of Voltage-gated K+ Channel Family 7 Embodies the Target Site for the Anticonvulsant Retigabine*

PubMed Central

Syeda, Ruhma; Santos, Jose S.; Montal, Mauricio

2016-01-01

KCNQ (voltage-gated K+ channel family 7 (Kv7)) channels control cellular excitability and underlie the K+ current sensitive to muscarinic receptor signaling (the M current) in sympathetic neurons. Here we show that the novel anti-epileptic drug retigabine (RTG) modulates channel function of pore-only modules (PMs) of the human Kv7.2 and Kv7.3 homomeric channels and of Kv7.2/3 heteromeric channels by prolonging the residence time in the open state. In addition, the Kv7 channel PMs are shown to recapitulate the single-channel permeation and pharmacological specificity characteristics of the corresponding full-length proteins in their native cellular context. A mutation (W265L) in the reconstituted Kv7.3 PM renders the channel insensitive to RTG and favors the conductive conformation of the PM, in agreement to what is observed when the Kv7.3 mutant is heterologously expressed. On the basis of the new findings and homology models of the closed and open conformations of the Kv7.3 PM, we propose a structural mechanism for the gating of the Kv7.3 PM and for the site of action of RTG as a Kv7.2/Kv7.3 K+ current activator. The results validate the modular design of human Kv channels and highlight the PM as a high-fidelity target for drug screening of Kv channels. PMID:26627826

Local anesthetic and antiepileptic drug access and binding to a bacterial voltage-gated sodium channel

PubMed Central

Boiteux, Céline; Vorobyov, Igor; French, Robert J.; French, Christopher; Yarov-Yarovoy, Vladimir; Allen, Toby W.

2014-01-01

Voltage-gated sodium (Nav) channels are important targets in the treatment of a range of pathologies. Bacterial channels, for which crystal structures have been solved, exhibit modulation by local anesthetic and anti-epileptic agents, allowing molecular-level investigations into sodium channel-drug interactions. These structures reveal no basis for the “hinged lid”-based fast inactivation, seen in eukaryotic Nav channels. Thus, they enable examination of potential mechanisms of use- or state-dependent drug action based on activation gating, or slower pore-based inactivation processes. Multimicrosecond simulations of NavAb reveal high-affinity binding of benzocaine to F203 that is a surrogate for FS6, conserved in helix S6 of Domain IV of mammalian sodium channels, as well as low-affinity sites suggested to stabilize different states of the channel. Phenytoin exhibits a different binding distribution owing to preferential interactions at the membrane and water–protein interfaces. Two drug-access pathways into the pore are observed: via lateral fenestrations connecting to the membrane lipid phase, as well as via an aqueous pathway through the intracellular activation gate, despite being closed. These observations provide insight into drug modulation that will guide further developments of Nav inhibitors. PMID:25136136

Turning Oscillations Into Opportunities: Lessons from a Bacterial Decision Gate

NASA Astrophysics Data System (ADS)

Schultz, Daniel; Lu, Mingyang; Stavropoulos, Trevor; Onuchic, Jose'; Ben-Jacob, Eshel

2013-04-01

Sporulation vs. competence provides a prototypic example of collective cell fate determination. The decision is performed by the action of three modules: 1) A stochastic competence switch whose transition probability is regulated by population density, population stress and cell stress. 2) A sporulation timer whose clock rate is regulated by cell stress and population stress. 3) A decision gate that is coupled to the timer via a special repressilator-like loop. We show that the distinct circuit architecture of this gate leads to special dynamics and noise management characteristics: The gate opens a time-window of opportunity for competence transitions during which it generates oscillations that are turned into a chain of transition opportunities - each oscillation opens a short interval with high transition probability. The special architecture of the gate also leads to filtering of external noise and robustness against internal noise and variations in the circuit parameters.

Turning Oscillations Into Opportunities: Lessons from a Bacterial Decision Gate

PubMed Central

Schultz, Daniel; Lu, Mingyang; Stavropoulos, Trevor; Onuchic, Jose'; Ben-Jacob, Eshel

2013-01-01

Sporulation vs. competence provides a prototypic example of collective cell fate determination. The decision is performed by the action of three modules: 1) A stochastic competence switch whose transition probability is regulated by population density, population stress and cell stress. 2) A sporulation timer whose clock rate is regulated by cell stress and population stress. 3) A decision gate that is coupled to the timer via a special repressilator-like loop. We show that the distinct circuit architecture of this gate leads to special dynamics and noise management characteristics: The gate opens a time-window of opportunity for competence transitions during which it generates oscillations that are turned into a chain of transition opportunities – each oscillation opens a short interval with high transition probability. The special architecture of the gate also leads to filtering of external noise and robustness against internal noise and variations in the circuit parameters. PMID:23591544

Pulsed dynamical decoupling for fast and robust two-qubit gates on trapped ions

NASA Astrophysics Data System (ADS)

Arrazola, I.; Casanova, J.; Pedernales, J. S.; Wang, Z.-Y.; Solano, E.; Plenio, M. B.

2018-05-01

We propose a pulsed dynamical decoupling protocol as the generator of tunable, fast, and robust quantum phase gates between two microwave-driven trapped-ion hyperfine qubits. The protocol consists of sequences of π pulses acting on ions that are oriented along an externally applied magnetic-field gradient. In contrast to existing approaches, in our design the two vibrational modes of the ion chain cooperate under the influence of the external microwave driving to achieve significantly increased gate speeds. Our scheme is robust against the dominant noise sources, which are errors on the magnetic-field and microwave pulse intensities, as well as motional heating, predicting two-qubit gates with fidelities above 99.9% in tens of microseconds.

CMOS integration of high-k/metal gate transistors in diffusion and gate replacement (D&GR) scheme for dynamic random access memory peripheral circuits

NASA Astrophysics Data System (ADS)

Dentoni Litta, Eugenio; Ritzenthaler, Romain; Schram, Tom; Spessot, Alessio; O’Sullivan, Barry; Machkaoutsan, Vladimir; Fazan, Pierre; Ji, Yunhyuck; Mannaert, Geert; Lorant, Christophe; Sebaai, Farid; Thiam, Arame; Ercken, Monique; Demuynck, Steven; Horiguchi, Naoto

2018-04-01

Integration of high-k/metal gate stacks in peripheral transistors is a major candidate to ensure continued scaling of dynamic random access memory (DRAM) technology. In this paper, the CMOS integration of diffusion and gate replacement (D&GR) high-k/metal gate stacks is investigated, evaluating four different approaches for the critical patterning step of removing the N-type field effect transistor (NFET) effective work function (eWF) shifter stack from the P-type field effect transistor (PFET) area. The effect of plasma exposure during the patterning step is investigated in detail and found to have a strong impact on threshold voltage tunability. A CMOS integration scheme based on an experimental wet-compatible photoresist is developed and the fulfillment of the main device metrics [equivalent oxide thickness (EOT), eWF, gate leakage current density, on/off currents, short channel control] is demonstrated.

Dynamical decoupling of local transverse random telegraph noise in a two-qubit gate

NASA Astrophysics Data System (ADS)

D'Arrigo, A.; Falci, G.; Paladino, E.

2015-10-01

Achieving high-fidelity universal two-qubit gates is a central requisite of any implementation of quantum information processing. The presence of spurious fluctuators of various physical origin represents a limiting factor for superconducting nanodevices. Operating qubits at optimal points, where the qubit-fluctuator interaction is transverse with respect to the single qubit Hamiltonian, considerably improved single qubit gates. Further enhancement has been achieved by dynamical decoupling (DD). In this article we investigate DD of transverse random telegraph noise acting locally on each of the qubits forming an entangling gate. Our analysis is based on the exact numerical solution of the stochastic Schrödinger equation. We evaluate the gate error under local periodic, Carr-Purcell and Uhrig DD sequences. We find that a threshold value of the number, n, of pulses exists above which the gate error decreases with a sequence-specific power-law dependence on n. Below threshold, DD may even increase the error with respect to the unconditioned evolution, a behaviour reminiscent of the anti-Zeno effect.

Chasing the open-state structure of pentameric ligand-gated ion channels

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gonzalez-Gutierrez, Giovanni; Wang, Yuhang; Cymes, Gisela D.

Remarkable advances have been made toward the structural characterization of ion channels in the last two decades. However, the unambiguous assignment of well-defined functional states to the obtained structural models has proved challenging. In the case of the superfamily of nicotinic-receptor channels (also referred to as pentameric ligand-gated ion channels [pLGICs]), for example, two different types of model of the open-channel conformation have been proposed on the basis of structures solved to resolutions better than 4.0 Å. At the level of the transmembrane pore, the open-state models of the proton-gated pLGIC fromGloeobacter violaceus(GLIC) and the invertebrate glutamate-gated Cl –channel (GluCl)more » are very similar to each other, but that of the glycine receptor (GlyR) is considerably wider. Indeed, the mean distances between the axis of ion permeation and the Cα atoms at the narrowest constriction of the pore (position -2') differ by ~2 Å in these two classes of model, a large difference when it comes to understanding the physicochemical bases of ion conduction and charge selectivity. Here, we take advantage of the extreme open-channel stabilizing effect of mutations at pore-facing position 9'. We find that the I9'A mutation slows down entry into desensitization of GLIC to the extent that macroscopic currents decay only slightly by the end of pH 4.5 solution applications to the extracellular side for several minutes. We crystallize (at pH 4.5) two variants of GLIC carrying this mutation and solve their structures to resolutions of 3.12 Å and 3.36 Å. Furthermore, we perform all-atom molecular dynamics simulations of ion permeation and picrotoxinin block, using the different open-channel structural models. On the basis of these results, we favor the notion that the open-channel structure of pLGICs from animals is much closer to that of the narrow models (of GLIC and GluCl) than it is to that of the GlyR.« less

Quasi-specific access of the potassium channel inactivation gate

PubMed Central

Venkataraman, Gaurav; Srikumar, Deepa; Holmgren, Miguel

2014-01-01

Many voltage-gated potassium channels open in response to membrane depolarization and then inactivate within milliseconds. Neurons use these channels to tune their excitability. In Shaker K+ channels, inactivation is caused by the cytoplasmic amino terminus, termed the inactivation gate. Despite having four such gates, inactivation is caused by the movement of a single gate into a position that occludes ion permeation. The pathway that this single inactivation gate takes into its inactivating position remains unknown. Here we show that a single gate threads through the intracellular entryway of its own subunit, but the tip of the gate has sufficient freedom to interact with all four subunits deep in the pore, and does so with equal probability. This pathway demonstrates that flexibility afforded by the inactivation peptide segment at the tip of the N-terminus is used to mediate function. PMID:24909510

Water Dynamics and Dewetting Transitions in the Small Mechanosensitive Channel MscS

PubMed Central

Anishkin, Andriy; Sukharev, Sergei

2004-01-01

The dynamics of confined water in capillaries and nanotubes suggests that gating of ion channels may involve not only changes of the pore geometry, but also transitions between water-filled and empty states in certain locations. The recently solved heptameric structure of the small mechanosensitive channel of Escherichia coli, MscS, has revealed a relatively wide (7–15 Å) yet highly hydrophobic transmembrane pore. Continuum estimations based on the properties of pore surface suggest low conductance and a thermodynamic possibility of dewetting. To test the predictions we performed molecular dynamics simulations of MscS filled with flexible TIP3P water. Irrespective to the initial conditions, several independent 6-ns simulations converged to the same stable state with the pore water-filled in the wider part, but predominantly empty in the narrow hydrophobic part, displaying intermittent vapor-liquid transitions. The polar gain-of-function substitution L109S in the constriction resulted in a stable hydration of the entire pore. Steered passages of Cl− ions through the narrow part of the pore consistently produced partial ion dehydration and required a force of 200–400 pN to overcome an estimated barrier of 10–20 kcal/mole, implying negligibly low conductance. We conclude that the crystal structure of MscS does not represent an open state. We infer that MscS gate, which is similar to that of the nicotinic ACh receptor, involves a vapor-lock mechanism where limited changes of geometry or surface polarity can locally switch the regime between water-filled (conducting) and empty (nonconducting) states. PMID:15111405

Exciton-Polariton Dynamics of a Monolayer Semiconductor Coupled to a Microcavity

NASA Astrophysics Data System (ADS)

Chen, Yen-Jung; Stanev, Teodor K.; Stern, Nathaniel P.; Cain, Jeffrey D.; Dravid, Vinayak P.

Strong light-matter interactions, evidenced by exciton-polariton states, have been observed in the two-dimensional limit with monolayer transition metal dichalcogenides (TMDs) embedded in a microcavity. Because of the valley degree of freedom in monolayer TMDs, these hybrid light-matter states can exhibit valley polarization as in a bare monolayer, with strongly-coupled dynamics determined by the relative rates of exciton relaxation and intervalley scattering, which can be highly modified in on-resonant cavities. Here, we test this intuitive picture of the polarized exciton-polariton dynamics with monolayer MoS2 coupled to detuned cavities. Upper and lower polariton branches exhibit distinct decay rates indicative of different cavity dynamics. As with on-resonant, strongly-coupled exciton-polaritons, the weakly-coupled regime causes exciton-polariton valley polarization to persist at room temperature, demonstrating that dynamics of valley-polarized excitations can be controlled by engineering light-matter interactions. This work is supported by the U.S. Department of Energy (BES DE-SC0012130) and the National Science Foundation MRSEC program (DMR-1121262). N.P.S. is an Alfred P. Sloan Research Fellow.

A dynamic wicking technique for determining the effective pore radius of pregelatinized starch sheets.

PubMed

Kalogianni, E P; Savopoulos, T; Karapantsios, T D; Raphaelides, S N

2004-06-01

A dynamic wicking technique is employed for the first time for the determination of the effective mean pore radius of a thin-layer porous food: drum dried pregelatinized starch sheets. The technique consists of measuring the penetration rate of various n-alkanes in the porous matrix of the starch sheets and using this data to calculate the effective pore radius via the Washburn equation. Pore sizes in the order of a few nanometers have been determined in the starch sheets depending on the drum dryer's operating variables (drum rotation speed, steam pressure and starch feed concentration). The conditions for the application of the technique in porous foods are discussed as compared to the conditions for single capillaries and inorganic porous material measured in other studies.

Exploring the Structure of the Voltage-gated Na+ Channel by an Engineered Drug Access Pathway to the Receptor Site for Local Anesthetics*

PubMed Central

Lukacs, Peter; Gawali, Vaibhavkumar S.; Cervenka, Rene; Ke, Song; Koenig, Xaver; Rubi, Lena; Zarrabi, Touran; Hilber, Karlheinz; Stary-Weinzinger, Anna; Todt, Hannes

2014-01-01

Despite the availability of several crystal structures of bacterial voltage-gated Na+ channels, the structure of eukaryotic Na+ channels is still undefined. We used predictions from available homology models and crystal structures to modulate an external access pathway for the membrane-impermeant local anesthetic derivative QX-222 into the internal vestibule of the mammalian rNaV1.4 channel. Potassium channel-based homology models predict amino acid Ile-1575 in domain IV segment 6 to be in close proximity to Lys-1237 of the domain III pore-loop selectivity filter. The mutation K1237E has been shown previously to increase the diameter of the selectivity filter. We found that an access pathway for external QX-222 created by mutations of Ile-1575 was abolished by the additional mutation K1237E, supporting the notion of a close spatial relationship between sites 1237 and 1575. Crystal structures of bacterial voltage-gated Na+ channels predict that the side chain of rNaV1.4 Trp-1531 of the domain IV pore-loop projects into the space between domain IV segment 6 and domain III pore-loop and, therefore, should obstruct the putative external access pathway. Indeed, mutations W1531A and W1531G allowed for exceptionally rapid access of QX-222. In addition, W1531G created a second non-selective ion-conducting pore, bypassing the outer vestibule but probably merging into the internal vestibule, allowing for control by the activation gate. These data suggest a strong structural similarity between bacterial and eukaryotic voltage-gated Na+ channels. PMID:24947510

Dynamically correcting two-qubit gates against any systematic logical error

NASA Astrophysics Data System (ADS)

Calderon Vargas, Fernando Antonio

The reliability of quantum information processing depends on the ability to deal with noise and error in an efficient way. A significant source of error in many settings is coherent, systematic gate error. This work introduces a set of composite pulse sequences that generate maximally entangling gates and correct all systematic errors within the logical subspace to arbitrary order. These sequences are applica- ble for any two-qubit interaction Hamiltonian, and make no assumptions about the underlying noise mechanism except that it is constant on the timescale of the opera- tion. The prime use for our results will be in cases where one has limited knowledge of the underlying physical noise and control mechanisms, highly constrained control, or both. In particular, we apply these composite pulse sequences to the quantum system formed by two capacitively coupled singlet-triplet qubits, which is charac- terized by having constrained control and noise sources that are low frequency and of a non-Markovian nature.

Coupling between electrolyte and organic semiconductor in electrolyte-gated organic field effect transistors (Conference Presentation)

NASA Astrophysics Data System (ADS)

Biscarini, Fabio; Di Lauro, Michele; Berto, Marcello; Bortolotti, Carlo A.; Geerts, Yves H.; Vuillaume, Dominique

2016-11-01

Organic field effect transistors (OFET) operated in aqueous environments are emerging as ultra-sensitive biosensors and transducers of electrical and electrochemical signals from a biological environment. Their applications range from detection of biomarkers in bodily fluids to implants for bidirectional communication with the central nervous system. They can be used in diagnostics, advanced treatments and theranostics. Several OFET layouts have been demonstrated to be effective in aqueous operations, which are distinguished either by their architecture or by the respective mechanism of doping by the ions in the electrolyte solution. In this work we discuss the unification of the seemingly different architectures, such as electrolyte-gated OFET (EGOFET), organic electrochemical transistor (OECT) and dual-gate ion-sensing FET. We first demonstrate that these architectures give rise to the frequency-dependent response of a synapstor (synapse-like transistor), with enhanced or depressed modulation of the output current depending on the frequency of the time-dependent gate voltage. This behavior that was reported for OFETs with embedded metal nanoparticles shows the existence of a capacitive coupling through an equivalent network of RC elements. Upon the systematic change of ions in the electrolyte and the morphology of the charge transport layer, we show how the time scale of the synapstor is changed. We finally show how the substrate plays effectively the role of a second bottom gate, whose potential is actually fixed by the pH/composition of the electrolyte and the gate voltage applied.

In situ pore-pressure evolution during dynamic CPT measurements in soft sediments of the western Baltic Sea

NASA Astrophysics Data System (ADS)

Seifert, Annedore; Stegmann, Sylvia; Mörz, Tobias; Lange, Matthias; Wever, Thomas; Kopf, Achim

2008-08-01

We present in situ strength and pore-pressure measurements from 57 dynamic cone penetration tests in sediments of Mecklenburg ( n = 51), Eckernförde ( n = 2) and Gelting ( n = 4) bays, western Baltic Sea, characterised by thick mud layers and partially free microbial gas resulting from the degradation of organic material. In Mecklenburg and Eckernförde bays, sediment sampling by nine gravity cores served sedimentological characterisation, analyses of geotechnical properties, and laboratory shear tests. At selected localities, high-resolution echo-sounder profiles were acquired. Our aim was to deploy a dynamic cone penetrometer (CPT) to infer sediment shear strength and cohesion of the sea bottom as a function of fluid saturation. The results show very variable changes in pore pressure and sediment strength during the CPT deployments. The majority of the CPT measurements ( n = 54) show initially negative pore-pressure values during penetration, and a delayed response towards positive pressures thereafter. This so-called type B pore-pressure signal was recorded in all three bays, and is typically found in soft muds with high water contents and undrained shear strengths of 1.6-6.4 kPa. The type B signal is further affected by displacement of sediment and fluid upon penetration of the lance, skin effects during dynamic profiling, enhanced consolidation and strength of individual horizons, the presence of free gas, and a dilatory response of the sediment. In Mecklenburg Bay, the remaining small number of CPT measurements ( n = 3) show a well-defined peak in both pore pressure and cone resistance during penetration, i.e. an initial marked increase which is followed by exponential pore-pressure decay during dissipation. This so-called type A pore-pressure signal is associated with normally consolidated mud, with indurated clay layers showing significantly higher undrained shear strength (up to 19 kPa). In Eckernförde and Gelting bays pore-pressure response type B is

Combining dynamic and ECG-gated ⁸²Rb-PET for practical implementation in the clinic.

PubMed

Sayre, George A; Bacharach, Stephen L; Dae, Michael W; Seo, Youngho

2012-01-01

For many cardiac clinics, list-mode PET is impractical. Therefore, separate dynamic and ECG-gated acquisitions are needed to detect harmful stenoses, indicate affected coronary arteries, and estimate stenosis severity. However, physicians usually order gated studies only because of dose, time, and cost limitations. These gated studies are limited to detection. In an effort to remove these limitations, we developed a novel curve-fitting algorithm [incomplete data (ICD)] to accurately calculate coronary flow reserve (CFR) from a combined dynamic-ECG protocol of a length equal to a typical gated scan. We selected several retrospective dynamic studies to simulate shortened dynamic acquisitions of the combined protocol and compared (a) the accuracy of ICD and a nominal method in extrapolating the complete functional form of arterial input functions (AIFs); and (b) the accuracy of ICD and ICD-AP (ICD with a-posteriori knowledge of complete-data AIFs) in predicting CFRs. According to the Akaike information criterion, AIFs predicted by ICD were more accurate than those predicted by the nominal method in 11 out of 12 studies. CFRs predicted by ICD and ICD-AP were similar to complete-data predictions (PICD=0.94 and PICD-AP=0.91) and had similar average errors (eICD=2.82% and eICD-AP=2.79%). According to a nuclear cardiologist and an expert analyst of PET data, both ICD and ICD-AP predicted CFR values with sufficient accuracy for the clinic. Therefore, by using our method, physicians in cardiac clinics would have access to the necessary amount of information to differentiate between single-vessel and triple-vessel disease for treatment decision making.

Structure-dependent water transport across nanopores of carbon nanotubes: toward selective gating upon temperature regulation.

PubMed

Zhao, Kuiwen; Wu, Huiying

2015-04-28

Determining water structure in nanopores and its influence on water transport behaviour is of great importance for understanding and regulating the transport across nanopores. Here we report an ultrafast-slow flow transition phenomenon for water transport across nanopores of carbon nanotubes owing to the change in water structure in nanopores induced by temperature. By performing extensive molecular dynamics simulations, we show the dependence of water transport behaviours on water structures. Our results indicate that owing to the change in water structure in nanopores, water flux across nanopores with certain pore sizes decreases sharply (nearly 3 orders of magnitude) with the decreasing temperature. This phenomenon is very sensitive to the pore size. The threshold temperatures for the occurrence of the ultrafast-slow flow transition for water transport are also determined for various pore sizes. These findings suggest a novel protocol for selective gating of water and proton conduction across nanopores and temperature-controlled drug release.

Dynamic coupled metal transport-speciation model: application to assess a zinc-contaminated lake.

PubMed

Bhavsar, Satyendra P; Diamond, Miriam L; Gandhi, Nilima; Nilsen, Joel

2004-10-01

A coupled metal transport and speciation/complexation model (TRANSPEC) has been developed to estimate the speciation and fate of multiple interconverting species in surface aquatic systems. Dynamic-TRANSPEC loosely, sequentially couples the speciation/complexation and fate modules that, for the unsteady state formulation, run alternatively at every time step. The speciation module first estimates species abundance using, in this version, MINEQL+ considering time-dependent changes in water and pore-water chemistry. The fate module is based on the quantitative water air sediment interaction (QWASI) model and fugacity/aquivalence formulation, with the option of using a pseudo-steady state solution to account for past discharges. Similarly to the QWASI model for organic contaminants, TRANSPEC assumes the instantaneous equilibrium distribution of metal species among dissolved, colloidal, and particulate phases based on ambient chemistry parameters that can be collected through conventional field methods. The model is illustrated with its application to Ross Lake (Manitoba, Canada) that has elevated Zn concentrations due to discharges over 70 years from a mining operation. Using measurements from field studies, the model reproduces year-round variations in Zn water concentrations. A 10-year projection for current conditions suggests decreasing Zn remobilization and export from the lake. Decreasing Zn loadings increases sediment-to-water transport but decreases water concentrations, and vice versa. Species distribution is affected by pH such that a decrease in pH increases metal export from the lake and vice versa.

The Influence of Pore Size on the Indentation Behavior of Metallic Nanoporous Materials: A Molecular Dynamics Study

PubMed Central

Esqué-de los Ojos, Daniel; Pellicer, Eva; Sort, Jordi

2016-01-01

In general, the influence of pore size is not considered when determining the Young’s modulus of nanoporous materials. Here, we demonstrate that the pore size needs to be taken into account to properly assess the mechanical properties of these materials. Molecular dynamics simulations of spherical indentation experiments on single crystalline nanoporous Cu have been undertaken in systems with: (i) a constant degree of porosity and variable pore diameter; and (ii) a constant pore diameter and variable porosity degree. The classical Gibson and Ashby expression relating Young’s modulus with the relative density of the nanoporous metal is modified to include the influence of the pore size. The simulations reveal that, for a fixed porosity degree, the mechanical behavior of materials with smaller pores differs more significantly from the behavior of the bulk, fully dense counterpart. This effect is ascribed to the increase of the overall surface area as the pore size is reduced, together with the reduced coordination number of the atoms located at the pores edges. PMID:28773476

Cadmium-cysteine coordination in the BK inner pore region and its structural and functional implications.

PubMed

Zhou, Yu; Xia, Xiao-Ming; Lingle, Christopher J

2015-04-21

To probe structure and gating-associated conformational changes in BK-type potassium (BK) channels, we examined consequences of Cd(2+) coordination with cysteines introduced at two positions in the BK inner pore. At V319C, the equivalent of valine in the conserved Kv proline-valine-proline (PVP) motif, Cd(2+) forms intrasubunit coordination with a native glutamate E321, which would place the side chains of V319C and E321 much closer together than observed in voltage-dependent K(+) (Kv) channel structures, requiring that the proline between V319C and E321 introduces a kink in the BK S6 inner helix sharper than that observed in Kv channel structures. At inner pore position A316C, Cd(2+) binds with modest state dependence, suggesting the absence of an ion permeation gate at the cytosolic side of BK channel. These results highlight fundamental structural differences between BK and Kv channels in their inner pore region, which likely underlie differences in voltage-dependent gating between these channels.

Molecular gated nanoporous anodic alumina for the detection of cocaine.

PubMed

Ribes, Àngela; Xifré-Pérez, Elisabet; Aznar, Elena; Sancenón, Félix; Pardo, Teresa; Marsal, Lluís F; Martínez-Máñez, Ramόn

2016-12-07

We present herein the use of nanoporous anodic alumina (NAA) as a suitable support to implement "molecular gates" for sensing applications. In our design, a NAA support is loaded with a fluorescent reporter (rhodamine B) and functionalized with a short single-stranded DNA. Then pores are blocked by the subsequent hybridisation of a specific cocaine aptamer. The response of the gated material was studied in aqueous solution. In a typical experiment, the support was immersed in hybridisation buffer solution in the absence or presence of cocaine. At certain times, the release of rhodamine B from pore voids was measured by fluorescence spectroscopy. The capped NAA support showed poor cargo delivery, but presence of cocaine in the solution selectively induced rhodamine B release. By this simple procedure a limit of detection as low as 5 × 10 -7  M was calculated for cocaine. The gated NAA was successfully applied to detect cocaine in saliva samples and the possible re-use of the nanostructures was assessed. Based on these results, we believe that NAA could be a suitable support to prepare optical gated probes with a synergic combination of the favourable features of selected gated sensing systems and NAA.

The S4–S5 Linker Acts as a Signal Integrator for hERG K+ Channel Activation and Deactivation Gating

PubMed Central

Ng, Chai Ann; Perry, Matthew D.; Tan, Peter S.; Hill, Adam P.; Kuchel, Philip W.; Vandenberg, Jamie I.

2012-01-01

Human ether-à-go-go-related gene (hERG) K+ channels have unusual gating kinetics. Characterised by slow activation/deactivation but rapid inactivation/recovery from inactivation, the unique gating kinetics underlie the central role hERG channels play in cardiac repolarisation. The slow activation and deactivation kinetics are regulated in part by the S4–S5 linker, which couples movement of the voltage sensor domain to opening of the activation gate at the distal end of the inner helix of the pore domain. It has also been suggested that cytosolic domains may interact with the S4–S5 linker to regulate activation and deactivation kinetics. Here, we show that the solution structure of a peptide corresponding to the S4–S5 linker of hERG contains an amphipathic helix. The effects of mutations at the majority of residues in the S4–S5 linker of hERG were consistent with the previously identified role in coupling voltage sensor movement to the activation gate. However, mutations to Ser543, Tyr545, Gly546 and Ala548 had more complex phenotypes indicating that these residues are involved in additional interactions. We propose a model in which the S4–S5 linker, in addition to coupling VSD movement to the activation gate, also contributes to interactions that stabilise the closed state and a separate set of interactions that stabilise the open state. The S4–S5 linker therefore acts as a signal integrator and plays a crucial role in the slow deactivation kinetics of the channel. PMID:22359612

Molecular dynamics and brownian dynamics investigation of ion permeation and anesthetic halothane effects on a proton-gated ion channel.

PubMed

Cheng, Mary Hongying; Coalson, Rob D; Tang, Pei

2010-11-24

Bacterial Gloeobacter violaceus pentameric ligand-gated ion channel (GLIC) is activated to cation permeation upon lowering the solution pH. Its function can be modulated by anesthetic halothane. In the present work, we integrate molecular dynamics (MD) and Brownian dynamics (BD) simulations to elucidate the ion conduction, charge selectivity, and halothane modulation mechanisms in GLIC, based on recently resolved X-ray crystal structures of the open-channel GLIC. MD calculations of the potential of mean force (PMF) for a Na(+) revealed two energy barriers in the extracellular domain (R109 and K38) and at the hydrophobic gate of transmembrane domain (I233), respectively. An energy well for Na(+) was near the intracellular entrance: the depth of this energy well was modulated strongly by the protonation state of E222. The energy barrier for Cl(-) was found to be 3-4 times higher than that for Na(+). Ion permeation characteristics were determined through BD simulations using a hybrid MD/continuum electrostatics approach to evaluate the energy profiles governing the ion movement. The resultant channel conductance and a near-zero permeability ratio (P(Cl)/P(Na)) were comparable to experimental data. On the basis of these calculations, we suggest that a ring of five E222 residues may act as an electrostatic gate. In addition, the hydrophobic gate region may play a role in charge selectivity due to a higher dehydration energy barrier for Cl(-) ions. The effect of halothane on the Na(+) PMF was also evaluated. Halothane was found to perturb salt bridges in GLIC that may be crucial for channel gating and open-channel stability, but had no significant impact on the single ion PMF profiles.

Dynamic Pore-Scale Imaging of Reactive Transport in Heterogeneous Carbonates at Reservoir Conditions Across Multiple Dissolution Regimes

NASA Astrophysics Data System (ADS)

Menke, H. P.; Bijeljic, B.; Andrew, M. G.; Blunt, M. J.

2014-12-01

Sequestering carbon in deep geologic formations is one way of reducing anthropogenic CO2 emissions. When supercritical CO2 mixes with brine in a reservoir, the acid generated has the potential to dissolve the surrounding pore structure. However, the magnitude and type of dissolution are condition dependent. Understanding how small changes in the pore structure, chemistry, and flow properties affect dissolution is paramount for successful predictive modelling. Both 'Pink Beam' synchrotron radiation and a Micro-CT lab source are used in dynamic X-ray microtomography to investigate the pore structure changes during supercritical CO2 injection in carbonate rocks of varying heterogeneity at high temperatures and pressures and various flow-rates. Three carbonate rock types were studied, one with a homogeneous pore structure and two heterogeneous carbonates. All samples are practically pure calcium carbonate, but have widely varying rock structures. Flow-rate was varied in three successive experiments by over an order of magnitude whlie keeping all other experimental conditions constant. A 4-mm carbonate core was injected with CO2-saturated brine at 10 MPa and 50oC. Tomographic images were taken at 30-second to 20-minute time-resolutions during a 2 to 4-hour injection period. A pore network was extracted using a topological analysis of the pore space and pore-scale flow modelling was performed directly on the binarized images with connected pathways and used to track the altering velocity distributions. Significant differences in dissolution type and magnitude were found for each rock type and flowrate. At the highest flow-rates, the homogeneous carbonate was seen to have predominately uniform dissolution with minor dissolution rate differences between the pores and pore throats. Alternatively, the heterogeneous carbonates which formed wormholes at high flow rates. At low flow rates the homogeneous rock developed wormholes, while the heterogeneous samples showed evidence

Disruption of the IS6-AID linker affects voltage-gated calcium channel inactivation and facilitation.

PubMed

Findeisen, Felix; Minor, Daniel L

2009-03-01

Two processes dominate voltage-gated calcium channel (Ca(V)) inactivation: voltage-dependent inactivation (VDI) and calcium-dependent inactivation (CDI). The Ca(V)beta/Ca(V)alpha(1)-I-II loop and Ca(2+)/calmodulin (CaM)/Ca(V)alpha(1)-C-terminal tail complexes have been shown to modulate each, respectively. Nevertheless, how each complex couples to the pore and whether each affects inactivation independently have remained unresolved. Here, we demonstrate that the IS6-alpha-interaction domain (AID) linker provides a rigid connection between the pore and Ca(V)beta/I-II loop complex by showing that IS6-AID linker polyglycine mutations accelerate Ca(V)1.2 (L-type) and Ca(V)2.1 (P/Q-type) VDI. Remarkably, mutations that either break the rigid IS6-AID linker connection or disrupt Ca(V)beta/I-II association sharply decelerate CDI and reduce a second Ca(2+)/CaM/Ca(V)alpha(1)-C-terminal-mediated process known as calcium-dependent facilitation. Collectively, the data strongly suggest that components traditionally associated solely with VDI, Ca(V)beta and the IS6-AID linker, are essential for calcium-dependent modulation, and that both Ca(V)beta-dependent and CaM-dependent components couple to the pore by a common mechanism requiring Ca(V)beta and an intact IS6-AID linker.

Disruption of the IS6-AID Linker Affects Voltage-gated Calcium Channel Inactivation and Facilitation

PubMed Central

Findeisen, Felix

2009-01-01

Two processes dominate voltage-gated calcium channel (CaV) inactivation: voltage-dependent inactivation (VDI) and calcium-dependent inactivation (CDI). The CaVβ/CaVα1-I-II loop and Ca2+/calmodulin (CaM)/CaVα1–C-terminal tail complexes have been shown to modulate each, respectively. Nevertheless, how each complex couples to the pore and whether each affects inactivation independently have remained unresolved. Here, we demonstrate that the IS6–α-interaction domain (AID) linker provides a rigid connection between the pore and CaVβ/I-II loop complex by showing that IS6-AID linker polyglycine mutations accelerate CaV1.2 (L-type) and CaV2.1 (P/Q-type) VDI. Remarkably, mutations that either break the rigid IS6-AID linker connection or disrupt CaVβ/I-II association sharply decelerate CDI and reduce a second Ca2+/CaM/CaVα1–C-terminal–mediated process known as calcium-dependent facilitation. Collectively, the data strongly suggest that components traditionally associated solely with VDI, CaVβ and the IS6-AID linker, are essential for calcium-dependent modulation, and that both CaVβ-dependent and CaM-dependent components couple to the pore by a common mechanism requiring CaVβ and an intact IS6-AID linker. PMID:19237593

A hydrophobic gate in an ion channel: the closed state of the nicotinic acetylcholine receptor

NASA Astrophysics Data System (ADS)

Beckstein, Oliver; Sansom, Mark S. P.

2006-06-01

The nicotinic acetylcholine receptor (nAChR) is the prototypic member of the 'Cys-loop' superfamily of ligand-gated ion channels which mediate synaptic neurotransmission, and whose other members include receptors for glycine, γ-aminobutyric acid and serotonin. Cryo-electron microscopy has yielded a three-dimensional structure of the nAChR in its closed state. However, the exact nature and location of the channel gate remains uncertain. Although the transmembrane pore is constricted close to its center, it is not completely occluded. Rather, the pore has a central hydrophobic zone of radius about 3 Å. Model calculations suggest that such a constriction may form a hydrophobic gate, preventing movement of ions through a channel. We present a detailed and quantitative simulation study of the hydrophobic gating model of the nicotinic receptor, in order to fully evaluate this hypothesis. We demonstrate that the hydrophobic constriction of the nAChR pore indeed forms a closed gate. Potential of mean force (PMF) calculations reveal that the constriction presents a barrier of height about 10 kT to the permeation of sodium ions, placing an upper bound on the closed channel conductance of 0.3 pS. Thus, a 3 Å radius hydrophobic pore can form a functional barrier to the permeation of a 1 Å radius Na+ ion. Using a united-atom force field for the protein instead of an all-atom one retains the qualitative features but results in differing conductances, showing that the PMF is sensitive to the detailed molecular interactions.

The Sensorless Pore Module of Voltage-gated K+ Channel Family 7 Embodies the Target Site for the Anticonvulsant Retigabine.

PubMed

Syeda, Ruhma; Santos, Jose S; Montal, Mauricio

2016-02-05

KCNQ (voltage-gated K(+) channel family 7 (Kv7)) channels control cellular excitability and underlie the K(+) current sensitive to muscarinic receptor signaling (the M current) in sympathetic neurons. Here we show that the novel anti-epileptic drug retigabine (RTG) modulates channel function of pore-only modules (PMs) of the human Kv7.2 and Kv7.3 homomeric channels and of Kv7.2/3 heteromeric channels by prolonging the residence time in the open state. In addition, the Kv7 channel PMs are shown to recapitulate the single-channel permeation and pharmacological specificity characteristics of the corresponding full-length proteins in their native cellular context. A mutation (W265L) in the reconstituted Kv7.3 PM renders the channel insensitive to RTG and favors the conductive conformation of the PM, in agreement to what is observed when the Kv7.3 mutant is heterologously expressed. On the basis of the new findings and homology models of the closed and open conformations of the Kv7.3 PM, we propose a structural mechanism for the gating of the Kv7.3 PM and for the site of action of RTG as a Kv7.2/Kv7.3 K(+) current activator. The results validate the modular design of human Kv channels and highlight the PM as a high-fidelity target for drug screening of Kv channels. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Magnetoelectric coupling of a magnetoelectric flux gate sensor in vibration noise circumstance

NASA Astrophysics Data System (ADS)

Chu, Zhaoqiang; Shi, Huaduo; Gao, Xiangyu; Wu, Jingen; Dong, Shuxiang

2018-01-01

A magnetoelectric (ME) flux gate sensor (MEFGS) consisting of piezoelectric PMN-PT single crystals and ferromagnetic amorphous alloy ribbon in a self-differential configuration is featured with the ability of weak magnetic anomaly detection. Here, we further investigated its ME coupling and magnetic field detection performance in vibration noise circumstance, including constant frequency, impact, and random vibration noise. Experimental results show that the ME coupling coefficient of MEFGS is as high as 5700 V/cm*Oe at resonant frequency, which is several orders magnitude higher than previously reported differential ME sensors. It was also found that under constant and impact vibration noise circumstance, the noise reduction and attenuation factor of MEFGS are over 17 and 85.7%, respectively. This work is important for practical application of MEFGS in real environment.

Smart Adsorbents with Photoregulated Molecular Gates for Both Selective Adsorption and Efficient Regeneration.

PubMed

Cheng, Lei; Jiang, Yao; Yan, Ni; Shan, Shu-Feng; Liu, Xiao-Qin; Sun, Lin-Bing

2016-09-07

Selective adsorption and efficient regeneration are two crucial issues for adsorption processes; unfortunately, only one of them instead of both is favored by traditional adsorbents with fixed pore orifices. Herein, we fabricated a new generation of smart adsorbents through grafting photoresponsive molecules, namely, 4-(3-triethoxysilylpropyl-ureido)azobenzene (AB-TPI), onto pore orifices of the support mesoporous silica. The azobenzene (AB) derivatives serve as the molecular gates of mesopores and are reversibly opened and closed upon light irradiation. Irradiation with visible light (450 nm) causes AB molecules to isomerize from cis to trans configuration, and the molecular gates are closed. It is easy for smaller adsorbates to enter while difficult for the larger ones, and the selective adsorption is consequently facilitated. Upon irradiation with UV light (365 nm), the AB molecules are transformed from trans to cis isomers, promoting the desorption of adsorbates due to the opened molecular gates. The present smart adsorbents can consequently benefit not only selective adsorption but also efficient desorption, which are exceedingly desirable for adsorptive separation but impossible for traditional adsorbents with fixed pore orifices.

A mechanism for acetylcholine receptor gating based on structure, coupling, phi, and flip

PubMed Central

Gupta, Shaweta; Chakraborty, Srirupa; Vij, Ridhima

2017-01-01

Nicotinic acetylcholine receptors are allosteric proteins that generate membrane currents by isomerizing (“gating”) between resting and active conformations under the influence of neurotransmitters. Here, to explore the mechanisms that link the transmitter-binding sites (TBSs) with the distant gate, we use mutant cycle analyses to measure coupling between residue pairs, phi value analyses to sequence domain rearrangements, and current simulations to reproduce a microsecond shut component (“flip”) apparent in single-channel recordings. Significant interactions between amino acids separated by >15 Å are rare; an exception is between the αM2–M3 linkers and the TBSs that are ∼30 Å apart. Linker residues also make significant, local interactions within and between subunits. Phi value analyses indicate that without agonists, the linker is the first region in the protein to reach the gating transition state. Together, the phi pattern and flip component suggest that a complete, resting↔active allosteric transition involves passage through four brief intermediate states, with brief shut events arising from sojourns in all or a subset. We derive energy landscapes for gating with and without agonists, and propose a structure-based model in which resting→active starts with spontaneous rearrangements of the M2–M3 linkers and TBSs. These conformational changes stabilize a twisted extracellular domain to promote transmembrane helix tilting, gate dilation, and the formation of a “bubble” that collapses to initiate ion conduction. The energy landscapes suggest that twisting is the most energetically unfavorable step in the resting→active conformational change and that the rate-limiting step in the reverse process is bubble formation. PMID:27932572

Mutations that stabilize the open state of the Erwinia chrisanthemi ligand-gated ion channel fail to change the conformation of the pore domain in crystals

PubMed Central

Gonzalez-Gutierrez, Giovanni; Lukk, Tiit; Agarwal, Vinayak; Papke, David; Nair, Satish K.; Grosman, Claudio

2012-01-01

The determination of structural models of the various stable states of an ion channel is a key step toward the characterization of its conformational dynamics. In the case of nicotinic-type receptors, different structures have been solved but, thus far, these different models have been obtained from different members of the superfamily. In the case of the bacterial member ELIC, a cysteamine-gated channel from Erwinia chrisanthemi, a structural model of the protein in the absence of activating ligand (and thus, conceivably corresponding to the closed state of this channel) has been previously generated. In this article, electrophysiological characterization of ELIC mutants allowed us to identify pore mutations that slow down the time course of desensitization to the extent that the channel seems not to desensitize at all for the duration of the agonist applications (>20 min). Thus, it seems reasonable to conclude that the probability of ELIC occupying the closed state is much lower for the ligand-bound mutants than for the unliganded wild-type channel. To gain insight into the conformation adopted by ELIC under these conditions, we solved the crystal structures of two of these mutants in the presence of a concentration of cysteamine that elicits an intracluster open probability of >0.9. Curiously, the obtained structural models turned out to be nearly indistinguishable from the model of the wild-type channel in the absence of bound agonist. Overall, our findings bring to light the limited power of functional studies in intact membranes when it comes to inferring the functional state of a channel in a crystal, at least in the case of the nicotinic-receptor superfamily. PMID:22474383

Cytoplasmic Domains and Voltage-Dependent Potassium Channel Gating

PubMed Central

Barros, Francisco; Domínguez, Pedro; de la Peña, Pilar

2012-01-01

The basic architecture of the voltage-dependent K+ channels (Kv channels) corresponds to a transmembrane protein core in which the permeation pore, the voltage-sensing components and the gating machinery (cytoplasmic facing gate and sensor–gate coupler) reside. Usually, large protein tails are attached to this core, hanging toward the inside of the cell. These cytoplasmic regions are essential for normal channel function and, due to their accessibility to the cytoplasmic environment, constitute obvious targets for cell-physiological control of channel behavior. Here we review the present knowledge about the molecular organization of these intracellular channel regions and their role in both setting and controlling Kv voltage-dependent gating properties. This includes the influence that they exert on Kv rapid/N-type inactivation and on activation/deactivation gating of Shaker-like and eag-type Kv channels. Some illustrative examples about the relevance of these cytoplasmic domains determining the possibilities for modulation of Kv channel gating by cellular components are also considered. PMID:22470342

Estimating Pore Properties from NMR Relaxation Time Measurements in Heterogeneous Media

NASA Astrophysics Data System (ADS)

Grunewald, E.; Knight, R.

2008-12-01

The link between pore geometry and the nuclear magnetic resonance (NMR) relaxation time T2 is well- established for simple systems but is poorly understood for complex media with heterogeneous pores. Conventional interpretation of NMR relaxation data employs a model of isolated pores in which each hydrogen proton samples only one pore type, and the T2-distribution is directly scaled to estimate a pore-size distribution. During an actual NMR measurement, however, each proton diffuses through a finite volume of the pore network, and so may sample multiple pore types encountered within this diffusion cell. For cases in which heterogeneous pores are strongly coupled by diffusion, the meaning of the T2- distribution is not well understood and further research is required to determine how such measurements should be interpreted. In this study we directly investigate the implications of pore coupling in two groups of laboratory NMR experiments. We conduct two suites of experiments, in which samples are synthesized to exhibit a range of pore coupling strengths using two independent approaches: (a) varying the scale of the diffusion cell and (b) varying the scale over which heterogeneous pores are encountered. In the first set of experiments, we vary the scale of the diffusion cell in silica gels which have a bimodal pore-size distribution comprised of intragrannular micropores and much larger intergrannular pores. The untreated gel exhibits strong pore coupling with a single broad peak observed in the T2-distribution. By treating the gel with varied amounts of paramagnetic iron surface coatings, we decrease the surface relaxation time, T2S, and effectively decrease both the size of the diffusion cell and the degree of pore coupling. As more iron is coated to the grain surfaces, we observe a separation of the broad T2-distribution into two peaks that more accurately represent the true bimodal pore-size distribution. In the second set of experiments, we vary the scale over

Voltage-dependent and -independent titration of specific residues accounts for complex gating of a ClC chloride channel by extracellular protons

PubMed Central

Niemeyer, María Isabel; Cid, L Pablo; Yusef, Yamil R; Briones, Rodolfo; Sepúlveda, Francisco V

2009-01-01

The ClC transport protein family comprises both Cl− ion channel and H+/Cl− and H+/NO3− exchanger members. Structural studies on a bacterial ClC transporter reveal a pore obstructed at its external opening by a glutamate side-chain which acts as a gate for Cl− passage and in addition serves as a staging post for H+ exchange. This same conserved glutamate acts as a gate to regulate Cl− flow in ClC channels. The activity of ClC-2, a genuine Cl− channel, has a biphasic response to extracellular pH with activation by moderate acidification followed by abrupt channel closure at pH values lower than ∼7. We have now investigated the molecular basis of this complex gating behaviour. First, we identify a sensor that couples extracellular acidification to complete closure of the channel. This is extracellularly-facing histidine 532 at the N-terminus of transmembrane helix Q whose neutralisation leads to channel closure in a cooperative manner. We go on to show that acidification-dependent activation of ClC-2 is voltage dependent and probably mediated by protonation of pore gate glutamate 207. Intracellular Cl− acts as a voltage-independent modulator, as though regulating the pKa of the protonatable residue. Our results suggest that voltage dependence of ClC-2 is given by hyperpolarisation-dependent penetration of protons from the extracellular side to neutralise the glutamate gate deep within the channel, which allows Cl− efflux. This is reminiscent of a partial exchanger cycle, suggesting that the ClC-2 channel evolved from its transporter counterparts. PMID:19153159

Experimental Quantification of Pore-Scale Flow Phenomena in 2D Heterogeneous Porous Micromodels: Multiphase Flow Towards Coupled Solid-Liquid Interactions

NASA Astrophysics Data System (ADS)

Li, Y.; Kazemifar, F.; Blois, G.; Christensen, K. T.

2017-12-01

Geological sequestration of CO2 within saline aquifers is a viable technology for reducing CO2 emissions. Central to this goal is accurately predicting both the fidelity of candidate sites pre-injection of CO2 and its post-injection migration. Moreover, local fluid pressure buildup may cause activation of small pre-existing unidentified faults, leading to micro-seismic events, which could prove disastrous for societal acceptance of CCS, and possibly compromise seal integrity. Recent evidence shows that large-scale events are coupled with pore-scale phenomena, which necessitates the representation of pore-scale stress, strain, and multiphase flow processes in large-scale modeling. To this end, the pore-scale flow of water and liquid/supercritical CO2 is investigated under reservoir-relevant conditions, over a range of wettability conditions in 2D heterogeneous micromodels that reflect the complexity of a real sandstone. High-speed fluorescent microscopy, complemented by a fast differential pressure transmitter, allows for simultaneous measurement of the flow field within and the instantaneous pressure drop across the micromodels. A flexible micromodel is also designed and fabricated, to be used in conjunction with the micro-PIV technique, enabling the quantification of coupled solid-liquid interactions.

The gating cycle of a K+ channel at atomic resolution

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cuello, Luis G.; Cortes, D. Marien; Perozo, Eduardo

C-type inactivation in potassium channels helps fine-tune long-term channel activity through conformational changes at the selectivity filter. Here, through the use of cross-linked constitutively open constructs, we determined the structures of KcsA’s mutants that stabilize the selectivity filter in its conductive (E71A, at 2.25 Å) and deep C-type inactivated (Y82A at 2.4 Å) conformations. These structural snapshots represent KcsA’s transient open-conductive (O/O) and the stable open deep C-type inactivated states (O/I), respectively. The present structures provide an unprecedented view of the selectivity filter backbone in its collapsed deep C-type inactivated conformation, highlighting the close interactions with structural waters and themore » local allosteric interactions that couple activation and inactivation gating. Together with the structures associated with the closed-inactivated state (C/I) and in the well-known closed conductive state (C/O), this work recapitulates, at atomic resolution, the key conformational changes of a potassium channel pore domain as it progresses along its gating cycle.« less

General implementation of arbitrary nonlinear quadrature phase gates

NASA Astrophysics Data System (ADS)

Marek, Petr; Filip, Radim; Ogawa, Hisashi; Sakaguchi, Atsushi; Takeda, Shuntaro; Yoshikawa, Jun-ichi; Furusawa, Akira

2018-02-01

We propose general methodology of deterministic single-mode quantum interaction nonlinearly modifying single quadrature variable of a continuous-variable system. The methodology is based on linear coupling of the system to ancillary systems subsequently measured by quadrature detectors. The nonlinear interaction is obtained by using the data from the quadrature detection for dynamical manipulation of the coupling parameters. This measurement-induced methodology enables direct realization of arbitrary nonlinear quadrature interactions without the need to construct them from the lowest-order gates. Such nonlinear interactions are crucial for more practical and efficient manipulation of continuous quadrature variables as well as qubits encoded in continuous-variable systems.

Vehicle systems: coupled and interactive dynamics analysis

NASA Astrophysics Data System (ADS)

Vantsevich, Vladimir V.

2014-11-01

This article formulates a new direction in vehicle dynamics, described as coupled and interactive vehicle system dynamics. Formalised procedures and analysis of case studies are presented. An analytical consideration, which explains the physics of coupled system dynamics and its consequences for dynamics of a vehicle, is given for several sets of systems including: (i) driveline and suspension of a 6×6 truck, (ii) a brake mechanism and a limited slip differential of a drive axle and (iii) a 4×4 vehicle steering system and driveline system. The article introduces a formal procedure to turn coupled system dynamics into interactive dynamics of systems. A new research direction in interactive dynamics of an active steering and a hybrid-electric power transmitting unit is presented and analysed to control power distribution between the drive axles of a 4×4 vehicle. A control strategy integrates energy efficiency and lateral dynamics by decoupling dynamics of the two systems thus forming their interactive dynamics.

1D-3D coupling for hydraulic system transient simulations

NASA Astrophysics Data System (ADS)

Wang, Chao; Nilsson, Håkan; Yang, Jiandong; Petit, Olivier

2017-01-01

This work describes a coupling between the 1D method of characteristics (MOC) and the 3D finite volume method of computational fluid dynamics (CFD). The coupling method is applied to compressible flow in hydraulic systems. The MOC code is implemented as a set of boundary conditions in the OpenFOAM open source CFD software. The coupling is realized by two linear equations originating from the characteristics equation and the Riemann constant equation, respectively. The coupling method is validated using three simple water hammer cases and several coupling configurations. The accuracy and robustness are investigated with respect to the mesh size ratio across the interface, and 3D flow features close to the interface. The method is finally applied to the transient flow caused by the closing and opening of a knife valve (gate) in a pipe, where the flow is driven by the difference in free surface elevation between two tanks. A small region surrounding the moving gate is resolved by CFD, using a dynamic mesh library, while the rest of the system is modeled by MOC. Minor losses are included in the 1D region, corresponding to the contraction of the flow from the upstream tank into the pipe, a separate stationary flow regulation valve, and a pipe bend. The results are validated with experimental data. A 1D solution is provided for comparison, using the static gate characteristics obtained from steady-state CFD simulations.

The Structural Basis of IKs Ion-Channel Activation: Mechanistic Insights from Molecular Simulations.

PubMed

Ramasubramanian, Smiruthi; Rudy, Yoram

2018-06-05

Relating ion channel (iCh) structural dynamics to physiological function remains a challenge. Current experimental and computational techniques have limited ability to explore this relationship in atomistic detail over physiological timescales. A framework associating iCh structure to function is necessary for elucidating normal and disease mechanisms. We formulated a modeling schema that overcomes the limitations of current methods through applications of artificial intelligence machine learning. Using this approach, we studied molecular processes that underlie human IKs voltage-mediated gating. IKs malfunction underlies many debilitating and life-threatening diseases. Molecular components of IKs that underlie its electrophysiological function include KCNQ1 (a pore-forming tetramer) and KCNE1 (an auxiliary subunit). Simulations, using the IKs structure-function model, reproduced experimentally recorded saturation of gating-charge displacement at positive membrane voltages, two-step voltage sensor (VS) movement shown by fluorescence, iCh gating statistics, and current-voltage relationship. Mechanistic insights include the following: 1) pore energy profile determines iCh subconductance; 2) the entire protein structure, not limited to the pore, contributes to pore energy and channel subconductance; 3) interactions with KCNE1 result in two distinct VS movements, causing gating-charge saturation at positive membrane voltages and current activation delay; and 4) flexible coupling between VS and pore permits pore opening at lower VS positions, resulting in sequential gating. The new modeling approach is applicable to atomistic scale studies of other proteins on timescales of physiological function. Copyright © 2018 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Restoration of rhythmicity in diffusively coupled dynamical networks.

PubMed

Zou, Wei; Senthilkumar, D V; Nagao, Raphael; Kiss, István Z; Tang, Yang; Koseska, Aneta; Duan, Jinqiao; Kurths, Jürgen

2015-07-15

Oscillatory behaviour is essential for proper functioning of various physical and biological processes. However, diffusive coupling is capable of suppressing intrinsic oscillations due to the manifestation of the phenomena of amplitude and oscillation deaths. Here we present a scheme to revoke these quenching states in diffusively coupled dynamical networks, and demonstrate the approach in experiments with an oscillatory chemical reaction. By introducing a simple feedback factor in the diffusive coupling, we show that the stable (in)homogeneous steady states can be effectively destabilized to restore dynamic behaviours of coupled systems. Even a feeble deviation from the normal diffusive coupling drastically shrinks the death regions in the parameter space. The generality of our method is corroborated in diverse non-linear systems of diffusively coupled paradigmatic models with various death scenarios. Our study provides a general framework to strengthen the robustness of dynamic activity in diffusively coupled dynamical networks.

Direct Evidence of Conformational Changes Associated with Voltage Gating in a Voltage Sensor Protein by Time-Resolved X-ray/Neutron Interferometry

PubMed Central

2015-01-01

The voltage sensor domain (VSD) of voltage-gated cation (e.g., Na+, K+) channels central to neurological signal transmission can function as a distinct module. When linked to an otherwise voltage-insensitive, ion-selective membrane pore, the VSD imparts voltage sensitivity to the channel. Proteins homologous with the VSD have recently been found to function themselves as voltage-gated proton channels or to impart voltage sensitivity to enzymes. Determining the conformational changes associated with voltage gating in the VSD itself in the absence of a pore domain thereby gains importance. We report the direct measurement of changes in the scattering-length density (SLD) profile of the VSD protein, vectorially oriented within a reconstituted phospholipid bilayer membrane, as a function of the transmembrane electric potential by time-resolved X-ray and neutron interferometry. The changes in the experimental SLD profiles for both polarizing and depolarizing potentials with respect to zero potential were found to extend over the entire length of the isolated VSD’s profile structure. The characteristics of the changes observed were in qualitative agreement with molecular dynamics simulations of a related membrane system, suggesting an initial interpretation of these changes in terms of the VSD’s atomic-level 3-D structure. PMID:24697545

A combined coarse-grained and all-atom simulation of TRPV1 channel gating and heat activation

PubMed Central

Qin, Feng

2015-01-01

The transient receptor potential (TRP) channels act as key sensors of various chemical and physical stimuli in eukaryotic cells. Despite years of study, the molecular mechanisms of TRP channel activation remain unclear. To elucidate the structural, dynamic, and energetic basis of gating in TRPV1 (a founding member of the TRPV subfamily), we performed coarse-grained modeling and all-atom molecular dynamics (MD) simulation based on the recently solved high resolution structures of the open and closed form of TRPV1. Our coarse-grained normal mode analysis captures two key modes of collective motions involved in the TRPV1 gating transition, featuring a quaternary twist motion of the transmembrane domains (TMDs) relative to the intracellular domains (ICDs). Our transition pathway modeling predicts a sequence of structural movements that propagate from the ICDs to the TMDs via key interface domains (including the membrane proximal domain and the C-terminal domain), leading to sequential opening of the selectivity filter followed by the lower gate in the channel pore (confirmed by modeling conformational changes induced by the activation of ICDs). The above findings of coarse-grained modeling are robust to perturbation by lipids. Finally, our MD simulation of the ICD identifies key residues that contribute differently to the nonpolar energy of the open and closed state, and these residues are predicted to control the temperature sensitivity of TRPV1 gating. These computational predictions offer new insights to the mechanism for heat activation of TRPV1 gating, and will guide our future electrophysiology and mutagenesis studies. PMID:25918362

Feedback coupling in dynamical systems

NASA Astrophysics Data System (ADS)

Trimper, Steffen; Zabrocki, Knud

2003-05-01

Different evolution models are considered with feedback-couplings. In particular, we study the Lotka-Volterra system under the influence of a cumulative term, the Ginzburg-Landau model with a convolution memory term and chemical rate equations with time delay. The memory leads to a modified dynamical behavior. In case of a positive coupling the generalized Lotka-Volterra system exhibits a maximum gain achieved after a finite time, but the population will die out in the long time limit. In the opposite case, the time evolution is terminated in a crash. Due to the nonlinear feedback coupling the two branches of a bistable model are controlled by the the strength and the sign of the memory. For a negative coupling the system is able to switch over between both branches of the stationary solution. The dynamics of the system is further controlled by the initial condition. The diffusion-limited reaction is likewise studied in case the reacting entities are not available simultaneously. Whereas for an external feedback the dynamics is altered, but the stationary solution remain unchanged, a self-organized internal feedback leads to a time persistent solution.

Application of Mortar Coupling in Multiscale Modelling of Coupled Flow, Transport, and Biofilm Growth in Porous Media

NASA Astrophysics Data System (ADS)

Laleian, A.; Valocchi, A. J.; Werth, C. J.

2017-12-01

Multiscale models of reactive transport in porous media are capable of capturing complex pore-scale processes while leveraging the efficiency of continuum-scale models. In particular, porosity changes caused by biofilm development yield complex feedbacks between transport and reaction that are difficult to quantify at the continuum scale. Pore-scale models, needed to accurately resolve these dynamics, are often impractical for applications due to their computational cost. To address this challenge, we are developing a multiscale model of biofilm growth in which non-overlapping regions at pore and continuum spatial scales are coupled with a mortar method providing continuity at interfaces. We explore two decompositions of coupled pore-scale and continuum-scale regions to study biofilm growth in a transverse mixing zone. In the first decomposition, all reaction is confined to a pore-scale region extending the transverse mixing zone length. Only solute transport occurs in the surrounding continuum-scale regions. Relative to a fully pore-scale result, we find the multiscale model with this decomposition has a reduced run time and consistent result in terms of biofilm growth and solute utilization. In the second decomposition, reaction occurs in both an up-gradient pore-scale region and a down-gradient continuum-scale region. To quantify clogging, the continuum-scale model implements empirical relations between porosity and continuum-scale parameters, such as permeability and the transverse dispersion coefficient. Solutes are sufficiently mixed at the end of the pore-scale region, such that the initial reaction rate is accurately computed using averaged concentrations in the continuum-scale region. Relative to a fully pore-scale result, we find accuracy of biomass growth in the multiscale model with this decomposition improves as the interface between pore-scale and continuum-scale regions moves downgradient where transverse mixing is more fully developed. Also, this

Gating, Regulation, and Structure in K2P K+ Channels: In Varietate Concordia?

PubMed

Niemeyer, María Isabel; Cid, L Pablo; González, Wendy; Sepúlveda, Francisco V

2016-09-01

K2P K(+) channels with two pore domains in tandem associate as dimers to produce so-called background conductances that are regulated by a variety of stimuli. Whereas gating in K2P channels has been poorly understood, recent developments have provided important clues regarding the gating mechanism for this family of proteins. Two modes of gating present in other K(+) channels have been considered. The first is the so-called activation gating that occurs by bundle crossing and the splaying apart of pore-lining helices commanding ion passage. The second mode involves a change in conformation at the selectivity filter (SF), which impedes ion flow at this narrow portion of the conduction pathway and accounts for extracellular pH modulation of several K2P channels. Although some evidence supports the existence of an activation gate in K2P channels, recent results suggest that perhaps all stimuli, even those sensed at a distant location in the protein, are also mediated by SF gating. Recently resolved crystal structures of K2P channels in conductive and nonconductive conformations revealed that the nonconductive state is reached by blockade by a lipid acyl chain that gains access to the channel cavity through intramembrane fenestrations. Here we discuss whether this novel type of gating, proposed so far only for membrane tension gating, might mediate gating in response to other stimuli or whether SF gating is the only type of opening/closing mechanism present in K2P channels. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Differential equations governing slip-induced pore-pressure fluctuations in a water-saturated granular medium

USGS Publications Warehouse

Iverson, R.M.

1993-01-01

Macroscopic frictional slip in water-saturated granular media occurs commonly during landsliding, surface faulting, and intense bedload transport. A mathematical model of dynamic pore-pressure fluctuations that accompany and influence such sliding is derived here by both inductive and deductive methods. The inductive derivation shows how the governing differential equations represent the physics of the steadily sliding array of cylindrical fiberglass rods investigated experimentally by Iverson and LaHusen (1989). The deductive derivation shows how the same equations result from a novel application of Biot's (1956) dynamic mixture theory to macroscopic deformation. The model consists of two linear differential equations and five initial and boundary conditions that govern solid displacements and pore-water pressures. Solid displacements and water pressures are strongly coupled, in part through a boundary condition that ensures mass conservation during irreversible pore deformation that occurs along the bumpy slip surface. Feedback between this deformation and the pore-pressure field may yield complex system responses. The dual derivations of the model help explicate key assumptions. For example, the model requires that the dimensionless parameter B, defined here through normalization of Biot's equations, is much larger than one. This indicates that solid-fluid coupling forces are dominated by viscous rather than inertial effects. A tabulation of physical and kinematic variables for the rod-array experiments of Iverson and LaHusen and for various geologic phenomena shows that the model assumptions commonly are satisfied. A subsequent paper will describe model tests against experimental data. ?? 1993 International Association for Mathematical Geology.

Gating currents from Kv7 channels carrying neuronal hyperexcitability mutations in the voltage-sensing domain.

PubMed

Miceli, Francesco; Vargas, Ernesto; Bezanilla, Francisco; Taglialatela, Maurizio

2012-03-21

Changes in voltage-dependent gating represent a common pathogenetic mechanism for genetically inherited channelopathies, such as benign familial neonatal seizures or peripheral nerve hyperexcitability caused by mutations in neuronal K(v)7.2 channels. Mutation-induced changes in channel voltage dependence are most often inferred from macroscopic current measurements, a technique unable to provide a detailed assessment of the structural rearrangements underlying channel gating behavior; by contrast, gating currents directly measure voltage-sensor displacement during voltage-dependent gating. In this work, we describe macroscopic and gating current measurements, together with molecular modeling and molecular-dynamics simulations, from channels carrying mutations responsible for benign familial neonatal seizures and/or peripheral nerve hyperexcitability; K(v)7.4 channels, highly related to K(v)7.2 channels both functionally and structurally, were used for these experiments. The data obtained showed that mutations affecting charged residues located in the more distal portion of S(4) decrease the stability of the open state and the active voltage-sensing domain configuration but do not directly participate in voltage sensing, whereas mutations affecting a residue (R4) located more proximally in S(4) caused activation of gating-pore currents at depolarized potentials. These results reveal that distinct molecular mechanisms underlie the altered gating behavior of channels carrying disease-causing mutations at different voltage-sensing domain locations, thereby expanding our current view of the pathogenesis of neuronal hyperexcitability diseases. Copyright © 2012 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Voltage- and ATP-dependent structural rearrangements of the P2X2 receptor associated with the gating of the pore

PubMed Central

Keceli, Batu; Kubo, Yoshihiro

2014-01-01

P2X2 is an extracellular ATP-gated cation channel which has a voltage-dependent gating property even though it lacks a canonical voltage sensor. It is a trimer in which each subunit has two transmembrane helices and a large extracellular domain. The three inter-subunit ATP binding sites are linked to the pore forming transmembrane (TM) domains by β-strands. We analysed structural rearrangements of the linker strands between the ATP binding site and TM domains upon ligand binding and voltage change, electrophysiologically in Xenopus oocytes, using mutants carrying engineered thiol-modifiable cysteine residues. (1) We demonstrated that the double mutant D315C&I67C (at β-14 and β-1, respectively) shows a 2- to 4-fold increase in current amplitude after treatment with a reducing reagent, dithiothreitol (DTT). Application of the thiol-reactive metal Cd2+ induced current decline due to bond formation between D315C and I67C. This effect was not observed in wild type (WT) or in single point mutants. (2) Cd2+-induced current decline was analysed in hyperpolarized and depolarized conditions with different pulse protocols, and also in the presence and absence of ATP. (3) Current decline induced by Cd2+ could be clearly observed in the presence of ATP, but was not clear in the absence of ATP, showing a state-dependent modification. (4) In the presence of ATP, Cd2+ modification was significantly faster in hyperpolarized than in depolarized conditions, showing voltage-dependent structural rearrangements of the linker strands. (5) Experiments using tandem trimeric constructs (TTCs) with controlled number and position of mutations in the trimer showed that the bridging by Cd2+ between 315 and 67 was not intra- but inter-subunit. (6) Finally, we performed similar analyses of a pore mutant T339S, which makes the channel activation voltage insensitive. Cd2+ modification rates of T339S were similar in hyperpolarized and depolarized conditions. Taking these results together, we

Scan direction induced charging dynamics and the application for detection of gate to S/D shorts in logic devices

NASA Astrophysics Data System (ADS)

Lei, Ming; Tian, Qing; Wu, Kevin; Zhao, Yan

2016-03-01

Gate to source/drain (S/D) short is the most common and detrimental failure mechanism for advanced process technology development in Metal-Oxide-Semiconductor-Field-Effect-Transistor (MOSFET) device manufacturing. Especially for sub-1Xnm nodes, MOSFET device is more vulnerable to gate-S/D shorts due to the aggressive scaling. The detection of this kind of electrical short defect is always challenging for in-line electron beam inspection (EBI), especially new shorting mechanisms on atomic scale due to new material/process flow implementation. The second challenge comes from the characterization of the shorts including identification of the exact shorting location. In this paper, we demonstrate unique scan direction induced charging dynamics (SDCD) phenomenon which stems from the transistor level response from EBI scan at post metal contact chemical-mechanical planarization (CMP) layers. We found that SDCD effect is exceptionally useful for gate-S/D short induced voltage contrast (VC) defect detection, especially for identification of shorting locations. The unique SDCD effect signatures of gate-S/D shorts can be used as fingerprint for ground true shorting defect detection. Correlation with other characterization methods on the same defective location from EBI scan shows consistent results from various shorting mechanism. A practical work flow to implement the application of SDCD effect for in-line EBI monitor of critical gate-S/D short defects is also proposed, together with examples of successful application use cases which mostly focus on static random-access memory (SRAM) array regions. Although the capability of gate-S/D short detection as well as expected device response is limited to passing transistors and pull-down transistors due to the design restriction from standard 6-cell SRAM structure, SDCD effect is proven to be very effective for gate-S/D short induced VC defect detection as well as yield learning for advanced technology development.

Voltage gating of mechanosensitive PIEZO channels.

PubMed

Moroni, Mirko; Servin-Vences, M Rocio; Fleischer, Raluca; Sánchez-Carranza, Oscar; Lewin, Gary R

2018-03-15

Mechanosensitive PIEZO ion channels are evolutionarily conserved proteins whose presence is critical for normal physiology in multicellular organisms. Here we show that, in addition to mechanical stimuli, PIEZO channels are also powerfully modulated by voltage and can even switch to a purely voltage-gated mode. Mutations that cause human diseases, such as xerocytosis, profoundly shift voltage sensitivity of PIEZO1 channels toward the resting membrane potential and strongly promote voltage gating. Voltage modulation may be explained by the presence of an inactivation gate in the pore, the opening of which is promoted by outward permeation. Older invertebrate (fly) and vertebrate (fish) PIEZO proteins are also voltage sensitive, but voltage gating is a much more prominent feature of these older channels. We propose that the voltage sensitivity of PIEZO channels is a deep property co-opted to add a regulatory mechanism for PIEZO activation in widely different cellular contexts.

Scanning gate imaging of two coupled quantum dots in single-walled carbon nanotubes.

PubMed

Zhou, Xin; Hedberg, James; Miyahara, Yoichi; Grutter, Peter; Ishibashi, Koji

2014-12-12

Two coupled single wall carbon nanotube quantum dots in a multiple quantum dot system were characterized by using a low temperature scanning gate microscopy (SGM) technique, at a temperature of 170 mK. The locations of single wall carbon nanotube quantum dots were identified by taking the conductance images of a single wall carbon nanotube contacted by two metallic electrodes. The single electron transport through single wall carbon nanotube multiple quantum dots has been observed by varying either the position or voltage bias of a conductive atomic force microscopy tip. Clear hexagonal patterns were observed in the region of the conductance images where only two sets of overlapping conductance rings are visible. The values of coupling capacitance over the total capacitance of the two dots, C(m)/C(1(2)) have been extracted to be 0.21 ∼ 0.27 and 0.23 ∼ 0.28, respectively. In addition, the interdot coupling (conductance peak splitting) has also been confirmed in both conductance image measurement and current-voltage curves. The results show that a SGM technique enables spectroscopic investigation of coupled quantum dots even in the presence of unexpected multiple quantum dots.

A two-phase debris-flow model that includes coupled evolution of volume fractions, granular dilatancy, and pore-fluid pressure

USGS Publications Warehouse

George, David L.; Iverson, Richard M.

2011-01-01

Pore-fluid pressure plays a crucial role in debris flows because it counteracts normal stresses at grain contacts and thereby reduces intergranular friction. Pore-pressure feedback accompanying debris deformation is particularly important during the onset of debrisflow motion, when it can dramatically influence the balance of forces governing downslope acceleration. We consider further effects of this feedback by formulating a new, depth-averaged mathematical model that simulates coupled evolution of granular dilatancy, solid and fluid volume fractions, pore-fluid pressure, and flow depth and velocity during all stages of debris-flow motion. To illustrate implications of the model, we use a finite-volume method to compute one-dimensional motion of a debris flow descending a rigid, uniformly inclined slope, and we compare model predictions with data obtained in large-scale experiments at the USGS debris-flow flume. Predictions for the first 1 s of motion show that increasing pore pressures (due to debris contraction) cause liquefaction that enhances flow acceleration. As acceleration continues, however, debris dilation causes dissipation of pore pressures, and this dissipation helps stabilize debris-flow motion. Our numerical predictions of this process match experimental data reasonably well, but predictions might be improved by accounting for the effects of grain-size segregation.

Synchronization Dynamics of Coupled Chemical Oscillators

NASA Astrophysics Data System (ADS)

Tompkins, Nathan

The synchronization dynamics of complex networks have been extensively studied over the past few decades due to their ubiquity in the natural world. Prominent examples include cardiac rhythms, circadian rhythms, the flashing of fireflies, predator/prey population dynamics, mammalian gait, human applause, pendulum clocks, the electrical grid, and of the course the brain. Detailed experiments have been done to map the topology of many of these systems and significant advances have been made to describe the mathematics of these networks. Compared to these bodies of work relatively little has been done to directly test the role of topology in the synchronization dynamics of coupled oscillators. This Dissertation develops technology to examine the dynamics due to topology within networks of discrete oscillatory components. The oscillatory system used here consists of the photo-inhibitable Belousov-Zhabotinsky (BZ) reaction water-in-oil emulsion where the oscillatory drops are diffusively coupled to one another and the topology is defined by the geometry of the diffusive connections. Ring networks are created from a close-packed 2D array of drops using the Programmable Illumination Microscope (PIM) in order to test Turing's theory of morphogenesis directly. Further technology is developed to create custom planar networks of BZ drops in more complicated topologies which can be individually perturbed using illumination from the PIM. The work presented here establishes the validity of using the BZ emulsion system with a PIM to study the topology induced effects on the synchronization dynamics of coupled chemical oscillators, tests the successes and limitations of Turing's theory of morphogenesis, and develops new technology to further probe the effects of network topology on a system of coupled oscillators. Finally, this Dissertation concludes by describing ongoing experiments which utilize this new technology to examine topology induced transitions of synchronization