Ion channels based on bis-macrocyclic bolaamphiphiles: effects of hydrophobic substitutions

1998 ◽  
Vol 76 (7) ◽  
pp. 1015-1026 ◽  
Author(s):  
T M Fyles ◽  
D Loock ◽  
X Zhou
Keyword(s):  
Electrostatic Interactions ◽  
Voltage Dependence ◽  
Bilayer Membrane ◽  
Time Signal ◽  
Head Group ◽  
Signal Shape ◽  
Current Time ◽  
Cation Selectivity ◽  
Rapid Current ◽  
New Compounds

Four new bis-macrocyclic bolaamphiphiles were prepared to explore the effects of hydrophobic substitutions on ion transport. In bilayer vesicles the new compounds were remarkably similar to more hydrophilic derivatives prepared previously. Planar bilayer conductance experiments showed the new compounds induced an unique current-time signal consisting of a rapid rise time, followed by a slower decay time. Signal shape was cation dependent and was related to a modest selectivity between cations. Cation-anion selectivity was very high, approaching an ideal cation selectivity. One compound also showed voltage dependence of the signal shape and duration. Qualitative changes in signal shape, duration, and voltage dependence were provoked by variation in the electrolyte pH and by masking the head-group electrostatic interactions with low levels of barium ions. A model for the signal shape is proposed, involving a rapid current rise due to aggregate restructuring, followed by slower decay due to development of the local Donnan potential that results from the high cation-anion selectivity.Key words: ion channel, synthesis, bilayer membrane, bilayer clamp, mechanism.

scholarly journals Polyunsaturated fatty acids produce a range of activators for heterogeneous IKs channel dysfunction

2019 ◽  
Vol 152 (2) ◽  
Author(s):  
Briana M. Bohannon ◽  
Xiaoan Wu ◽  
Xiongyu Wu ◽  
Marta E. Perez ◽  
Sara I. Liin ◽  
...  
Keyword(s):  
Ventricular Arrhythmias ◽  
Electrostatic Interactions ◽  
Voltage Dependence ◽  
Delayed Rectifier ◽  
Head Group ◽  
Maximal Conductance ◽  
Head Groups ◽  
K Current ◽  
Iks Channel ◽  
Congenital Long Qt Syndrome

Repolarization and termination of the ventricular cardiac action potential is highly dependent on the activation of the slow delayed-rectifier potassium IKs channel. Disruption of the IKs current leads to the most common form of congenital long QT syndrome (LQTS), a disease that predisposes patients to ventricular arrhythmias and sudden cardiac death. We previously demonstrated that polyunsaturated fatty acid (PUFA) analogues increase outward K+ current in wild type and LQTS-causing mutant IKs channels. Our group has also demonstrated the necessity of a negatively charged PUFA head group for potent activation of the IKs channel through electrostatic interactions with the voltage-sensing and pore domains. Here, we test whether the efficacy of the PUFAs can be tuned by the presence of different functional groups in the PUFA head, thereby altering the electrostatic interactions of the PUFA head group with the voltage sensor or the pore. We show that PUFA analogues with taurine and cysteic head groups produced the most potent activation of IKs channels, largely by shifting the voltage dependence of activation. In comparison, the effect on voltage dependence of PUFA analogues with glycine and aspartate head groups was half that of the taurine and cysteic head groups, whereas the effect on maximal conductance was similar. Increasing the number of potentially negatively charged moieties did not enhance the effects of the PUFA on the IKs channel. Our results show that one can tune the efficacy of PUFAs on IKs channels by altering the pKa of the PUFA head group. Different PUFAs with different efficacy on IKs channels could be developed into more personalized treatments for LQTS patients with a varying degree of IKs channel dysfunction.

scholarly journals Molecular dynamics simulations and experimental studies reveal differential permeability of withaferin-A and withanone across the model cell membrane

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Renu Wadhwa ◽  
Neetu Singh Yadav ◽  
Shashank P. Katiyar ◽  
Tomoko Yaguchi ◽  
Chohee Lee ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Cell Membrane ◽  
Molecular Dynamics Simulations ◽  
Experimental Studies ◽  
Bilayer Membrane ◽  
Withaferin A ◽  
Head Group ◽  
Polar Head Group ◽  
Natural Drugs ◽  
Dynamics Simulations

AbstractPoor bioavailability due to the inability to cross the cell membrane is one of the major reasons for the failure of a drug in clinical trials. We have used molecular dynamics simulations to predict the membrane permeability of natural drugs—withanolides (withaferin-A and withanone) that have similar structures but remarkably differ in their cytotoxicity. We found that whereas withaferin-A, could proficiently transverse through the model membrane, withanone showed weak permeability. The free energy profiles for the interaction of withanolides with the model bilayer membrane revealed that whereas the polar head group of the membrane caused high resistance for the passage of withanone, the interior of the membrane behaves similarly for both withanolides. The solvation analysis further revealed that the high solvation of terminal O5 oxygen of withaferin-A was the major driving force for its high permeability; it interacted with the phosphate group of the membrane that led to its smooth passage across the bilayer. The computational predictions were tested by raising and recruiting unique antibodies that react to withaferin-A and withanone. The time-lapsed analyses of control and treated cells demonstrated higher permeation of withaferin-A as compared to withanone. The concurrence between the computation and experimental results thus re-emphasised the use of computational methods for predicting permeability and hence bioavailability of natural drug compounds in the drug development process.

scholarly journals Interactions of Visinin-like Proteins with Phospho-inositides

2010 ◽  
Vol 63 (3) ◽  
pp. 350 ◽  
Author(s):  
Karl-Heinz Braunewell ◽  
Blessy Paul ◽  
Wassim Altarche-Xifro ◽  
Cornelia Noack ◽  
Kristian Lange ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Electrostatic Interactions ◽  
Specific Binding ◽  
Surface Membrane ◽  
Living Cells ◽  
Head Group ◽  
Subcellular Membrane ◽  
Monolayer Adsorption ◽  
Lysine Residues ◽  
Phosphatidylinositol Phosphates

The subcellular membrane localization of neuronal calcium sensor (NCS) proteins in living cells, such as Visinin-like Proteins-1 (VILIP-1) and VILIP-3, differs substantially. We have followed the hypothesis that the differential localization may be due to the specific binding capabilities of individual VILIPs for phosphatidylinositol phosphates (PIPs). Several highly conserved lysine residues in the N-terminal region could provide favourable electrostatic interactions. Molecular modelling results support a binding site for phospho-inositides in the N-terminal area of VILIP-1, and the involvement of the conserved N-terminal lysine residues in binding the phospho-inositol head group. Experimentally, the binding of VILIP-1 to inositol derivatives was tested by a PIP strip assay, which showed the requirement of phosphorylation of the inositol group for the interaction of the protein with PIPs. Monolayer adsorption measurements showed a preference of VILIP-1 binding to PI(4,5)P2 over PI(3,4,5)P3. The co-localization of VILIP-1 with PI(4,5)P2 at the cell surface membrane in hippocampal neurons further supports the idea of direct interactions of VILIP-1 with PIPs in living cells.

scholarly journals Shaker potassium channel gating. II: Transitions in the activation pathway.

1994 ◽  
Vol 103 (2) ◽  
pp. 279-319 ◽  
Author(s):  
W N Zagotta ◽  
T Hoshi ◽  
J Dittman ◽  
R W Aldrich
Keyword(s):  
Conformational Changes ◽  
Time Course ◽  
Voltage Dependence ◽  
Single Channel ◽  
Ionic Current ◽  
Activation Process ◽  
Charge Movement ◽  
Open Probability ◽  
Current Time ◽  
Gating Charge

Voltage-dependent gating behavior of Shaker potassium channels without N-type inactivation (ShB delta 6-46) expressed in Xenopus oocytes was studied. The voltage dependence of the steady-state open probability indicated that the activation process involves the movement of the equivalent of 12-16 electronic charges across the membrane. The sigmoidal kinetics of the activation process, which is maintained at depolarized voltages up to at least +100 mV indicate the presence of at least five sequential conformational changes before opening. The voltage dependence of the gating charge movement suggested that each elementary transition involves 3.5 electronic charges. The voltage dependence of the forward opening rate, as estimated by the single-channel first latency distribution, the final phase of the macroscopic ionic current activation, the ionic current reactivation and the ON gating current time course, showed movement of the equivalent of 0.3 to 0.5 electronic charges were associated with a large number of the activation transitions. The equivalent charge movement of 1.1 electronic charges was associated with the closing conformational change. The results were generally consistent with models involving a number of independent and identical transitions with a major exception that the first closing transition is slower than expected as indicated by tail current and OFF gating charge measurements.

scholarly journals Different Head Group Dependence on The Lipid Thermodynamic Property of Myelin Basic Protein in the Lipid Monolayer

2021 ◽  
Author(s):  
Lei Zhang ◽  
Ming Zhang ◽  
Runguang Sun
Keyword(s):  
Myelin Basic Protein ◽  
Electrostatic Interactions ◽  
Basic Protein ◽  
Second Virial Coefficient ◽  
Virial Equation ◽  
Lipid Monolayer ◽  
Statistical Thermodynamic ◽  
Head Group ◽  
Myelin Lipid ◽  
Head Groups

Abstract The interaction between the role of 18.5 KDa myelin basic protein (MBP) isoform and phospholipids has been thought to maintain the stability and compactness of the myelin sheath structure. In this study, we describe the statistical thermodynamic theory of different concentrations’ effects on MBP in the major myelin lipid (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE)，and 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine (POPS)) monolayers at the air/subphase interface via Langmuir-Blodgett (LB) technique. A simple statistical mechanical theory is established that predicts the interaction between proteins and phosphate head groups at low surface pressures and the second virial coefficient dependences for the PC, PE, and PS head groups are illustrated. In addition, the surface pressure(π)-mean molecular area(mma) curves were also analyzed using two-dimensional virial equation of state (2D-VES). The positively charged showed that MBP may integrate into different lipid monolayers via hydrophobic and electrostatic interactions, which was found to be consistent with AFM observations of domain and aggregate structures as well as with changes in the surface morphology induced by MBP. These analyses pertaining to membrane structure will provide better insight into membrane modeling systems, especially the interaction between membrane molecules.

scholarly journals Synthesis, Characterization and Encapsulation of Novel Plant Growth Regulators (PGRs) in Biopolymer Matrices

2020 ◽  
Author(s):  
Kristina Vlahoviček-Kahlina ◽  
Slaven Jurić ◽  
Marijan Marijan ◽  
Botagoz Mutaliyeva ◽  
Svetlana Khalus ◽  
...  
Keyword(s):  
Plant Growth ◽  
Plant Growth Regulators ◽  
Growth Regulators ◽  
Electrostatic Interactions ◽  
Growth Regulation ◽  
Field Experiments ◽  
Dimethyl Ester ◽  
Plant Growth Regulation ◽  
New Compounds ◽  
Derivatives Of

Abstract Novel plant growth regulators (PGRs) based on the derivatives of dehydroamino acids (2,3-dehydroaspartic acid dimethyl ester, Z-isomer of the potassium salt of 2-amino-3-methoxycarbonylacrylic acid and 1-methyl-3-methylamino-maleimide) have been synthesized and their growth-regulating properties investigated. Laboratory testing and field experiments revealed new compounds are highly effective environmentally friendly plant growth regulators with effects on different crops. Biopolymeric microcapsule formulations (chitosan/alginate microcapsule loaded with PGR) suitable for application in agriculture were prepared and characterized. Physicochemical properties and release profiles of PGRs from microcapsule formulations depend on the molecular interactions between microcapsule constituents including mainly electrostatic interactions and hydrogen bonds. The differences in the microcapsule formulations structure did not affect the mechanism of PGRs release which was identified as diffusion through microcapsules. The obtained results opened a perspective for the future use of microcapsule formulations as new promising agroformulations with a sustained and target release for plant growth regulation.

scholarly journals Interaction of metalloporphyrins with lipid bilayers, a calorimetric study

2011 ◽  
Vol 34 (1) ◽  
pp. 11-14
Author(s):  
Katarzyna Pamin ◽  
Jan Połtowicz ◽  
Joanna Kiełkowicz ◽  
Andrzej Hendrich
Keyword(s):  
Experimental Data ◽  
Phase Transitions ◽  
Lipid Bilayer ◽  
Lipid Bilayers ◽  
Electrostatic Interactions ◽  
Acyl Chain ◽  
Head Group ◽  
Calorimetric Study ◽  
Polar Head Group ◽  
Polar Head

Interaction of metalloporphyrins with lipid bilayers, a calorimetric studyThe interaction of three metalloporphyrins, containing manganese, iron and cobalt atoms, with lipid bilayers composed of neutral (DPPC) or charged (DMPG) phospholipids were studied by means of scanning differential calorimetry. We found only minute effects exerted by studied compounds on DPPC, while phase transitions of charged DMPG were seriously affected by porphyrins. Analysis of experimental data revealed that due to the electrostatic interactions DMPG bilayers are perturbed not only in the polar head group region. Putative rearrangements of the polar heads packing affects also the acyl chain region of this lipid bilayer. Perturbation of DMPG polar heads induced by porphyrin in complex with manganese atoms is bigger than that induced by other porphyrins.

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