Dynamics Of Gate Research Articles

Lipid-Mediated Helix Gating in the GlpG Rhomboid Protease from Escherichia Coli

Intramembrane proteases cleave transmembrane substrates to liberate molecules that participate in essential cellular processes, such as cell signaling and gene regulation. Understanding how intramembrane proteases work requires knowledge of how substrates are docked and cleaved within the membrane plane. We find that lipid interactions and the presence of the substrate affect significantly the structure and dynamics of the helical gate and of the cap loop that control access to the active site of the GlpG rhomboid protease from E. coli.In the absence of the substrate, the 1-palmytoyl-2-oleoyl-sn-glycero-3-phosphatidyethanolamine (POPE) lipid molecule bound to the protease active site remains closely associated with the protease on the ∼90ns timescale of the molecular dynamics (MD) simulation. Presence of the Spitz transmembrane substrate perturbs the interactions between the protease and the active-site lipid molecule. The substrate and whether or not a lipid headgroup is bound to the active site affect the orientation of the lateral gate helix 5 relative to the rest of the protein, the structure and dynamics of the cap loop, and the interaction between the catalytic serine and water. This suggests that lipid molecules may be involved in controlling the access to the active site of intramembrane proteases.This research was supported in part by the National Institute of General Medical Sciences (GM-74637 and GM-86685 to S.H.W) and an allocation of computer time from the National Science Foundation through the TeraGrid resources at TACC (Ranger).

Insights into the Mechanism of Release of Substrate in the Inward Facing Glutamate Transporter from Molecular Dynamics Simulations

Glutamate transporters regulate neurotransmission across glial and neuronal cell membranes, by actively coupling to the energetically favorable transport of cations including sodium or potassium and/or protons. Previous simulations of the outward facing glutamate transporter GltpH from Pyrococuss Horikoshii (PDB ID 1xfh) (Shrivastava et al, J. Biol. Chem. ,2008), revealed the mechanism of substrate diffusion and binding at the binding site. The binding was facilitated by the intrinsic dynamics of the extracellular gate, comprised of a hairpin loop, HP2. In the inward facing structure of the same protein, (PDB ID 3KBC) the transport machinery comprising of TM7, HP1,HP2 and TM8 is translated by almost 15 A[[Unsupported Character - ]]downwards towards the intracellular side, with respect to the outward facing structure. Fifty nanosecond simulations each, of the Apo_MD (no substrate or sodium ions in the core), Na_MD (only sodium ions in the core) and the Asp_Na_MD (substrate and sodium ions in the core) were performed, in a fully atomistic, solvated bilayer environment. In the Apo_MD and the Na_MD simulations, the HP1 loop has a much higher mobility than the HP2 loop. However, the release of the substrate into the intracellular solvent in Asp_Na_MD, required the motions of both the HP1 and the HP2 loops. The opening up of HP2 loop facilitates solvation of the binding site resulting in the substrate being dislodged from its position. Prior to substrate release, the HP1 loop moves further down into the solvent, exposing the HP1-tip and the substrate to the solvent, followed by its subsequent release into the intracellular solvent. These results suggest that the intracellular gating involves sequential opening of both HP1 and HP2 loops.

Aminocalix[4]arene: the effect of pH on the dynamics of gate and portals on the hydrophobic cavity

The pH of a solution shows a significant effect on the dynamics of the gate (formed by eight benzylic functions) and portal on the hydrophobic cavity of receptor. At pH 5.8 the gate closes and prohibits the entry of anionic guests. However, at pH 7.3 the gate opens and allows the entry of anionic guests into the hydrophobic cavity. It is the first time that anionic receptor efficiently recognizes anionic guests.

All-Atom Molecular Dynamics Simulations of the K+ Channel Chimera Kv1.2/Kv2.1

Voltage-gated K+ channels (Kv) are composed of four subunits, each of which contains six trans-membrane domains (TMs), S1 through S6. The S1-S4 segments comprise the voltage-sensing domain (VS), which senses membrane potential and controls the gating of the pore domain (PD). Although still controversial, the voltage-sensing domain undergoes conformational changes within the membrane electric field, upon membrane depolarization, that is mechanically transferred via the S4-S5 linker to the intracellular gate of the channel. MD simulations of portions of PD and VS regions highlighted the importance of their flexibility for proper channel function. Nevertheless, a comprehensive description of the dynamics of both domains at atomic level has not been provided yet. Here we report the analysis of all-atom multiple molecular dynamics simulations (∼200 ns) of the entire Kv1.2/2.1 chimera, consisting of the α and β chain embedded in a 549 monomer POPC bilayer, and immersed in a box of 135K explicit SPC water molecules at 300 K. We used principal components analysis (PCA) of the Cα atomic fluctuations covariance matrix to analyze the essential subspace that characterizes the channel internal dynamics. Briefly, we observed an up to 4.5 A conformational drift of VS from its starting position. The average RMSF of the S3b-S4 domain was between 1.6 and 3.0 A. Relative to the pore region, i) the second principal component shows that all four VS domains fluctuate in a concerted manner and affect the flexibility of the intracellular gates; ii) the first principal component reveals that T1 domain moves approximately 3.5 A downwards, influencing the local structure and dynamics of the neighboring intracellular gate. Protein-lipids interactions are crucial for channel structure/function. Thus, the contributions of H-bonds and salt-bridges between channel atoms and lipid head-groups on global channel dynamics will be illustrated.

Topo2008: DNA Topoisomerases in Biology and Medicine

Topo2008: DNA Topoisomerases in Biology and Medicine

Dynamical regimes of a quantum SWAP gate beyond the Fermi golden rule

We discuss how the bath's memory affects the dynamics of a SWAP gate. We present an exactly solvable model that shows various dynamical transitions when treated beyond the Fermi golden rule. By moving continuously a single parameter, the unperturbed Rabi frequency, we sweep through different analytic properties of the density of states: (I) collapsed resonances that split at an exceptional point in (II) two resolved resonances; (III) out-of-band resonances; (IV) virtual states; and (V) pure point spectrum. We associate them with distinctive dynamical regimes: overdamped, damped oscillations, environment controlled quantum diffusion, anomalous diffusion, and localized dynamics, respectively. The frequency of the SWAP gate depends differently on the unperturbed Rabi frequency. In region I there is no oscillation at all, while in the regions III and IV the oscillation frequency is particularly stable because it is determined by the environment's band width. The anomalous diffusion could be used as a signature for the presence of the elusive virtual states.

Dynamics of the Extracellular Gate and Ion-Substrate Coupling in the Glutamate Transporter

Glutamate transporters (GluTs) are the primary regulators of extracellular concentration of the neurotransmitter glutamate in the central nervous system. In this study, we have investigated the dynamics and coupling of the substrate and Na + binding sites, and the mechanism of cotransport of Na + ions, using molecular dynamics simulations of a membrane-embedded model of GluT in its apo (empty form) and various Na +- and/or substrate-bound states. The results shed light on the mechanism of the extracellular gate and on the sequence of binding of the substrate and Na + ions to GluT during the transport cycle. The results suggest that the helical hairpin HP2 plays the key role of the extracellular gate for the substrate binding site, and that the opening and closure of the gate is controlled by substrate binding. GluT adopts an open conformation in the absence of the substrate exposing the binding sites of the substrate and Na + ions to the extracellular solution. Based on the calculated trajectories, we propose that Na1 is the first element to bind GluT, as it is found to be important for the completion of the substrate binding site. The subsequent binding of the substrate, in turn, is shown to result in an almost complete closure of the extracellular gate and the formation of the Na2 binding site. Finally, binding of Na2 locks the extracellular gate and completes the formation of the occluded state of GluT.

Single spin Toffoli–Fredkin logic gate

The Toffoli–Fredkin (TF) gate is a universal reversible logic gate capable of performing logic operations without dissipating energy. Here, we show that a linear array of three quantum dots, each hosting a single electron, can realize the TF gate, if we encode logic bits in the spin polarization of the electrons and allow nearest neighbor exchange coupling. The dynamics of the TF gate is realized by selectively driving spin resonances in the coupled spin system with an ac magnetic field. The conditions for gate operation are established, and an estimate of the switching speed and gate error are provided.

Manifold algorithmic errors in quantum computers with static internal imperfections

The inevitable existence of static internal imperfections and residual interactions in some quantum computer architectures results in internal decoherence, dissipation and destructive unitary shifts of active algorithms. By exact numerical simulations, we determine the relative importance and origin of these errors for a Josephson charge-qubit quantum computer. In particular we determine that the dynamics of a CNOT gate interacting with its idle neighboring qubits via native residual coupling behaves much like a perturbed kicked top in the exponential decay regime, where fidelity decay is only weakly dependent on perturbation strength. This means that retroactive removal of gate errors (whether unitary or non-unitary) may not be possible, and that effective error correction schemes must operate concurrently with the implementation of subcomponents of the gate.

Signatures of a quantum dynamical phase transition in a three-spin system in presence of a spin environment

We have observed an environmentally induced quantum dynamical phase transition in the dynamics of a two-spin experimental swapping gate [G.A. Álvarez, E.P. Danieli, P.R. Levstein, H.M. Pastawski, J. Chem. Phys. 124 (2006) 194507]. There, the exchange of the coupled states | ↑ , ↓ 〉 and | ↓ , ↑ 〉 gives an oscillation with a Rabi frequency b / ℏ (the spin-spin coupling). The interaction, ℏ / τ SE with a spin-bath degrades the oscillation with a characteristic decoherence time. We showed that the swapping regime is restricted only to b τ SE ≳ ℏ . However, beyond a critical interaction with the environment the swapping freezes and the system enters to a Quantum Zeno dynamical phase where relaxation decreases as coupling with the environment increases. Here, we solve the quantum dynamics of a two-spin system coupled to a spin-bath within a Liouville–von Neumann quantum master equation and we compare the results with our previous work within the Keldysh formalism. Then, we extend the model to a three interacting spin system where only one is coupled to the environment. Beyond a critical interaction the two spins not coupled to the environment oscillate with the bare Rabi frequency and relax more slowly. This effect is more pronounced when the anisotropy of the system-environment (SE) interaction goes from a purely XY to an Ising interaction form.

Conformational dynamics of the major yeast phosphatidylinositol transfer protein sec14p: insight into the mechanisms of phospholipid exchange and diseases of sec14p-like protein deficiencies.

Molecular dynamics simulations coupled with functional analyses of the major yeast phosphatidylinositol/phosphatidylcholine transfer protein Sec14p identify structural elements involved in regulating the ability of Sec14p to execute phospholipid exchange. The molecular dynamics simulations suggest large rigid body motions within the Sec14p molecule accompany closing and opening of an A(10)/T(4)/A(11) helical gate, and that "state-of-closure" of this helical gate determines access to the Sec14p phospholipid binding cavity. The data also project that conformational dynamics of the helical gate are controlled by a hinge unit (residues F(212), Y(213), K(239), I(240), and I(242)) that links to the N- and C-terminal ends of the helical gate, and by a novel gating module (composed of the B(1)LB(2) and A(12)LT(5) substructures) through which conformational information is transduced to the hinge. The (114)TDKDGR(119) motif of B(1)LB(2) plays an important role in that transduction process. These simulations offer new mechanistic possibilities for an important half-reaction of the Sec14p phospholipid exchange cycle that occurs on membrane surfaces after Sec14p has ejected bound ligand, and is reloading with another phospholipid molecule. These conformational transitions further suggest structural rationales for known disease missense mutations that functionally compromise mammalian members of the Sec14-protein superfamily.

Quantum dynamical phase transition in a system with many-body interactions

Recent experiments, [G.A. Álvarez, E.P. Danieli, P.R. Levstein, H.M. Pastawski, J. Chem. Phys. 124 (2006) 194507], have reported the observation of a quantum dynamical phase transition in the dynamics of a spin swapping gate. In order to explain this result from a microscopic perspective, we introduce a Hamiltonian model of a two level system with many-body interactions with an environment whose excitation dynamics is fully solved within the Keldysh formalism. If a particle starts in one of the states of the isolated system, the return probability oscillates with the Rabi frequency ω 0 . For weak interactions with the environment 1 / τ SE < 2 ω 0 , we find a slower oscillation whose amplitude decays with a rate 1 / τ ϕ = 1 / ( 2 τ SE ) . However, beyond a finite critical interaction with the environment, 1 / τ SE > 2 ω 0 , the decay rate becomes 1 / τ ϕ ∝ ω 0 2 τ SE . The oscillation period diverges showing a quantum dynamical phase transition to a Quantum Zeno phase consistent with the experimental observations.

Molecular Modeling and Dynamics of the Sodium Channel Inactivation Gate

The intracellular linker L III-IV of voltage-gated sodium channels is known to be involved in their mechanism of inactivation. Its primary sequence is well conserved in sodium channels from different tissues and species. However, the role of charged residues in this region, first thought to play an important role in inactivation, has not been well identified, whereas the IFM triad (I1488-M1490) has been characterized as the crucial element for inactivation. In this work, we constructed theoretical models and performed molecular dynamics simulations, exploring the role of L III-IV-charged residues in the presence of a polar/nonpolar planar interface represented by a dielectric discontinuity. From structural predictions, two α-helical segments are proposed. Moreover, from dynamics simulations, a time-conserved motif is detected and shown to play a relevant role in guiding the inactivation particle toward its receptor site.

Dynamics of a quantum control-not gate for an ensemble of four-spin molecules at room temperature

We investigate numerically a single-electromagnetic-pulse implementation of a quantum control-not (CN) gate for an ensemble of Ising spin systems at room temperature. For an ensemble of four-spin ``molecules'' we simulate the time evolution of the density matrix for both digital and superpositional initial conditions. Our numerical calculations confirm the feasibility of implementation of a quantum CN gate in this system at finite temperature, using a single electromagnetic \ensuremath{\pi} pulse. We also study the quantum dynamics of creating entangled states in a macroscopic paramagnetic spin system at low temperatures, and compare the related quantum and corresponding classical dynamics. In the quantum case, one can create entangled states using a resonant interaction between the spin system and the electromagnetic \ensuremath{\pi} pulse. In the classical limit, the interaction of the spin system with the same pulse becomes nonresonant and the corresponding classical dynamics differs significantly from the quantum dynamics. This difference in the behavior of the macroscopic magnetization can be used in experiments as an indication of the existence of entangled states.

Dynamics of a Control-Not gate for a quantum system of two weakly interacting spins

We present the results of computer simulations of dynamics of the quantum Control-Not gate for the system of two spins connected by a weak Ising interaction. It is demonstrated that, for both “digital” and “superposition” initial conditions, 3 resonant π-pulse can provide an adequate implementation of the quantum Control-Not gate. We also consider the influence of slightly non-resonant π-pulse and noise on the dynamics of the quantum Control-Not gate.

The Thalamic Intralaminar Nuclei: A Role in Visual Awareness

We briefly review the anatomy and functional properties of the intralaminar nuclei (ILN) of the thalamus and the neurological disorders associated with their dysfunction. The ILN project over a wide range of cortical territories and are connected to several subcortical structures that place the ILN within the distributed networks underlying arousal, attention, working memory, and gaze control. The temporal structure of the spike discharges of ILN neurons can be controlled by levels of arousal and visuomotor behavior. Taken together, the anatomy, cellular physiology, and clinical data suggest that in the state of wakefulness, the ILN neurons promote the formation of an “event-holding” function in the cortex. In the prefrontal cortex, this function facilitates the storage of target location in working memory. In the frontal eye fields, the function produces sustained activation that anticipates the onset of intended eye movements. In the posterior parietal cortex, the sustained activation can be boosted at the start of the intersaccadic interval and can operate as an attentional gate regulating the flow of information back to the prefrontal cortex. The attentional gate is of limited capacity, as is working memory, and is best utilized during the intersaccadic interval. The ILN may help to synchronize the eye movement commands of the frontal eye fields with the episodic dynamics of the attentional gate and working memory.