Ion-pair Interactions Research Articles

Quaternary diammonium reagents hosted on polymer nanofibers for hexachloridoiridate(IV) specificity: Experimental and theoretical studies

This study is focused on the development of iridium(IV)-specific quaternary diammonium cations containing electron-donating and electron-withdrawing groups. Quaternary diammonium cations used were tetramethylbenzyl-1,10-diammonium decane chloride (QuatDMDAMeBnz), tetrabenzyl-1,10-diammonium decane chloride (QuatDMDABnz), tetratrifluoromethylbenzyl-1,10-diammonium chloride (QuatDMDACF3Bnz), and tetranitrobenzyl-1,10-diammonium chloride (QuatDMDANO2Bnz). Polyvinylbenzylchloride (PVBC) nanofibers were used as a support material, and the functionalised nanofibers were used for the separation of Ir(IV) from Rh(III). The efficiency of the quaternary diammonium cations was investigated in a column study under dynamic flow adsorption conditions. Column sorption of [IrCl6]2- and [RhCl5(H2O)]2- on nanofibers functionalized with diammonium cations showed [RhCl5(H2O)]2- was not adsorbed by the sorbent materials while [IrCl6]2- was loaded onto the column. The loading capacities of [IrCl6]2- on the quaternary diammonium sorbent materials increased in the order of F-QuatDMDAMeBnz (3.08 mg/g; 16.01 mmol/g) < F-QuatDMDABnz (3.39 mg/g; 17.63 mmol/g) < F-QuatDMDACF3Bnz (5.46 mg/g; 28.42 mmol/g) < F-QuatDMDANO2Bnz (7.10 mg/g; 36.96 mmol/g). The loading capacity for Ir(IV) with quaternary diammonium cationic nanofibers increased with an increase in the electron-withdrawing nature of the substituent on the quaternizing group. This trend was further explained by considering the anion binding energies and electrostatic charges of the diammonium cations as well as their ion-pairing interactions with [IrCl6]2- and [RhCl5(H2O)]2- using molecular modeling calculations. The formation of [(L)IrCl6] ion-pairs with the charge diffuse [IrCl6]2- anion was energetically favoured from QuatDMDAMeBnz to QuatDMDANO2Bnz. The positive electrostatic potential (ESP) values of 473.92 kcal/mol for QuatDMDAMeBnz, 495.85 kcal/mol for QuatDMDABnz, 991.12 kcal/mol for QuatDMDACF3Bnz and 1133.05 kcal/mol for QuatDMDANO2Bnz also followed this trend. This trend was also well correlated with binding energies of the respective cations with [IrCl6]2- which were 22.66 kcal/mol for QuatDMDAMeBnz, 27.43 kcal/mol for QuatDMDABnz, 49.19 kcal/mol for QuatDMDACF3Bnz and 51.04 kcal/mol for QuatDMDANO2Bnz.

Filtering the NMR Spectra of Mixtures by Coordination to Paramagnetic Cu2.

The paramagnetic spin relaxation (PSR) filter allows the selective NMR signal suppression of components in mixtures according to their complexation ability to a paramagnetic ion. It relies on the faster relaxation of nuclei in paramagnetic environments and thus is complementary to classical diffusion and relaxation filters. So far, the PSR filter has established Gd3+ as the sole PSR agent, restricting the paramagnetic filtering repertoire. Herein, we present Cu2+ as a robust PSR agent with characteristic filtering properties. While Gd3+ depends on unspecific ion-pair interactions with anionic components, Cu2+ stands out for filtering species via ordered coordination complexes. An evaluation of the paramagnetic effect of Cu2+ over more than 50 small molecules and polymers has unveiled different sensitivities to Cu2+ (especially high for pyridines, diamines, polyamines, and amino alcohols) and precise filtering conditions for mixtures (1H, COSY, and HMQC) that were challenged with a test bed of commercial drugs. The advantage of integrating Cu2+ and Gd3+ for the stepwise PSR filtering of complex mixtures is also shown.

The Effects of Charged Amino Acid Side-Chain Length on Diagonal Cross-Strand Interactions between Carboxylate- and Ammonium-Containing Residues in a β-Hairpin.

The β-sheet is one of the common protein secondary structures, and the aberrant aggregation of β-sheets is implicated in various neurodegenerative diseases. Cross-strand interactions are an important determinant of β-sheet stability. Accordingly, both diagonal and lateral cross-strand interactions have been studied. Surprisingly, diagonal cross-strand ion-pairing interactions have yet to be investigated. Herein, we present a systematic study on the effects of charged amino acid side-chain length on a diagonal ion-pairing interaction between carboxylate- and ammonium-containing residues in a β-hairpin. To this end, 2D-NMR was used to investigate the conformation of the peptides. The fraction folded population and the folding free energy were derived from the chemical shift data. The fraction folded population for these peptides with potential diagonal ion pairs was mostly lower compared to the corresponding peptide with a potential lateral ion pair. The diagonal ion-pairing interaction energy was derived using double mutant cycle analysis. The Asp2-Dab9 (Asp: one methylene; Dab: two methylenes) interaction was the most stabilizing (−0.79 ± 0.14 kcal/mol), most likely representing an optimal balance between the entropic penalty to enable the ion-pairing interaction and the number of side-chain conformations that can accommodate the interaction. These results should be useful for designing β-sheet containing molecular entities for various applications.

New Developments in Chiral Phosphoric Acid Catalysis for Amine Synthesis

Abstract:Asymmetric catalysis with chiral phosphoric acids (CPAs) has impacted a wide range of organic reactions, including those that generate chiral amines of interest in medicinal and natural products chemistry. Phosphodiester derivatives (RO)2PO2H offer linkages to various chiral alcohols and diols, permitting the CPA to transmit stereochemical information to reactants via ion-pairing and/or H-bonding interactions of the P=O and O–H bonds. This minireview presents selected recent developments in CPA-catalyzed asymmetric synthesis of amines, emphasizing innovations from the literature of 2017–2021, with a few earlier examples to provide additional context. The coverage includes additions to imines, asymmetric protonation, induction of axial asymmetry, asymmetric Ugi and Passerini multicomponent coupling reactions, hydroaminations, and Minisci-type additions to heteroaromatic systems.

Adsorptive removal of fluoride using ionic liquid-functionalized chitosan – Equilibrium and mechanism studies

In this study, novel biosorbents, based on chitosan and imidazolium ionic liquid, were prepared for the removal of fluoride from aqueous solutions. The adsorbents were characterized by FTIR, SEM-EDS and low-temperature nitrogen adsorption-desorption. To investigate the adsorption mechanism and behavior of chitosan adsorbents, batch experiments were conducted under different adsorbent dosages (2, 4, 10 g/L), pH (4, 7, 9) and initial concentration (0.5–25.0 mg/L). The influence of the method of synthesis of ionic liquid on the adsorption performance were also studied. Experimental data were evaluated by Freundlich, Langmuir and Sips models. The introduction of ionic liquid significantly improved the uptake of fluoride compared to pure chitosan. The adsorption was influenced by the experimental conditions, as well as the method of ionic liquid synthesis. The highest fluoride removal was observed at pH 4 and found to decrease with increasing pH. The removal efficiency and adsorption capacity values indicated that the dose of 4 g/L was the optimum adsorbent dosage. The equilibrium data fitted best with the Sips isotherm and the maximum adsorption capacity reached 8.068 mg/g for modified chitosan beads. The mechanism of fluoride adsorption onto ionic liquid-modified chitosan involves electrostatic attraction, ion exchange and ion pair interaction.

Quantification of Water–Ion Pair Interactions in Polyelectrolyte Multilayers Using a Quartz Crystal Microbalance Method

Water existing within thin polyelectrolyte multilayer (PEM) films has significant influence on their physical, chemical, and thermal properties, having implications for applications including energy storage, smart coatings, and biomedical systems. Ionic strength, salt type, and terminating layer are known to influence PEM swelling. However, knowledge of water’s microenvironment within a PEM, whether that water is affiliated with intrinsic or extrinsic ion pairs, remains lacking. Here, we examine the influence of both assembly and post-assembly conditions on the water–ion pair interactions of poly(styrene sulfonate)/poly(diallyldimethylammonium) (PSS/PDADMA) PEMs in NaCl and KBr. This is accomplished by developing a methodology in which quartz crystal microbalance with dissipation monitoring is applied to estimate the number of water molecules affiliated with an ion pair (i), as well as the hydration coefficient, πsaltH2O. PSS/PDADMA PEMs are assembled in varying ionic strengths of either NaCl and KBr and then exposed post-assembly to increasing ionic strengths of matching salt type. A linear relationship between the total amount of water per intrinsic ion pair and the post-assembly salt concentration was obtained at post-assembly salt concentrations >0.5 M, yielding estimates for both i and πsaltH2O. We observe higher values of i and πsaltH2O in KBr-assembled PEMs due to KBr being more effective in doping the assembly because of KBr’s more chaotropic nature as compared to NaCl. Lastly, when PSS is the terminating layer, i decreases in value due to PSS’s hydrophobic nature. Classical and ab initio molecular dynamics provide a microstructural view as to how NaCl and KBr interact with individual polyelectrolytes and the involved water shells. Put together, this study provides further insight into the understanding of existing water microenvironments in PEMs and the effects of both assembly and post-assembly conditions.

Development of C2-Symmetric Chiral Diphosphine Ligands for Highly Enantioselective Hydrogenation Assisted by Ion Pairing.

A new series of C2-symmetrical chiral ferrocene-based diphosphino-ethane ligands termed as f-DPE were developed. Assisted by the ion pairing interaction with the ligand, a wide scope of 2-substituted acrylic acids was hydrogenated to obtain chiral propanoic acids with high yields and enantioselectivities. The well-known anti-inflammatory drugs ibuprofen, naproxen, and flurbiprofen could be synthesized efficiently. In addition, the synthetic utilities of the current method were demonstrated by gram-scale experiments.

Adopted ion-pair effect to construct bicontinuous starch-based gel and its application in humidity sensitivity and strain-responsiveness

Along with the growing consume of disposable electronic devices, the development of biodegradable and sustainable resources is highly desired to address the contaminated footprints from petroleum-based materials. However, it is still a challenge to overcome obstacles of the dispersion of additives and flexibility for fabricating starch-based strain-responsiveness device. Herein, we developed a facile method to fabricate mechanically stretchable starch-based gel (SGZn gel) with humidity-conductivity through thermal mixing starch and ions-pairing solution, which was a kind of transparent gel without region of stress concentration and hysteresis effect. Attributed to disorganization effect and dipole interaction of ion pairs, SGZn gels achieved homogeneous matrix, increased elongation at break (243%) and high transparency (87%). Meanwhile, the continuous ionic conductivity paths in gel matrix constructed by ions-pairing solution could endow SGZn gels with excellent humidity sensitivity, obtaining an ionic conductivity of 10−3 S/cm after absorbing 10 wt% water from humidity environment. Benefiting from these features, SGZn gels were capable of sensing human motions, both tiny motion in fingers and intense force in feet, satisfying the basic requirements for sustainable wearable devices. This study provided a facile approach for preparing multifunctional starch-based gels to meet the requirements in various applications such as flexible material, humidity detection and smart devices.

Analyte Interactions with Oxoporphyrinogen Derivatives: Computational Aspects

Abstract: The binding of anions by highly-coloured chromophore compounds is of interest from the point-of-view of the development of optical sensors for analyte species. In this review, we have summarised our work on the interactions between oxoporphyrinogen type host compounds and different analyte species using computational methods. The origin of our interest in sensing using oxoporphyrinogens stems from an initial finding involving anionhost interactions involving a conjugated oxoporphyrinogen molecule. This review starts from that point, introducing some additional exemplary anion binding data, which is then elaborated to include descriptions of our synthesis work towards multitopic and ion pair interactions. In all the projects, we have consulted computational data on host structure and hostguest complexes in order to obtain information about the interactions occurring during complexation. Density functional theory and molecular dynamics simulations have been extensively used for these purposes.

Metal‐Supported Phospholipid Bilayers Formed by Redox Command (Adv. Mater. Interfaces 6/2022)

A Surface Redox Reaction Lays Down Lipid Membranes In article number 2101289, Ons Hmam and Antonella Badia demonstrate the assembly of single bilayer membranes within minutes at room temperature from phospholipid vesicles in the gel or fluid phase via ion-pairing interactions between the charged lipid head groups and electrogenerated cationic ferroceniums bound to a self-assembled monolayer.

Ion-Pairing Reagent Free Hydrophilic Interaction LC-MS/MS Method for Therapeutic Drug Monitoring of Amikacin in Neonates

Synthesis and Evaluation of new Ethyl N-[(Z)-(2-Oxo-5-Sulfamoyl-Indolin-3-Ylidene) Amino] Carbamate Derivatives for their Antimicrobial and Anti-inflammatory ActivitySrikanth Lingala, Kiran Samudrala, Raghunandan Nerella

Study on interactions of amino acid with food additive ammonium acetate: An environment friendly approach

Considering the biological importance of amino acids and proteins, the objective of this work is to study the physico-chemical and thermodynamic properties of amino acid with food additives. Volumetric studies were performed on a nonessential amino acid, glutamic acid (Glu) solutions of different concentrations in water and aqueous ammonium acetate (AA) at T = 293.15–313.15 K. AA is used as a biodegradable deicing agent. Parameters like density, apparent molar volume and partial molar volume conclude that stronger ion-ion, ion-hydrophilic and hydrophilic-hydrophilic interactions between zwitterionic centers (COO- and NH3+) and polar groups of Glu (COOH and NH2) and ions present in aqueous AA dominate the hydrophobic interactions. Structure making or breaking properties of Glu in absence and in presence of AA in solution were estimated in terms of temperature derivatives of apparent molar volume at infinite dilution. Glu is found to act as a structure maker in aqueous solution whereas the presence of ions of AA hinders the structure making ability of Glu. Existence of ion pair interactions are established between ionic end groups of Glu and AA in solution. The results of the study showed the type and extent of interactions between Glu and AA and suggest that appropriate quantity of food additives should be present in water bodies to minimize toxicity of aquatic environment.

Surface Engineering Assisted Size and Structure Modulation of Gold Nanoclusters by Ionic Liquid Cations.

Surface modification induced core size/structure change is a recent discovery in inorganic nanoparticles research, and has rarely been revealed at the molecular level. Here, we exemplify with atomically precise Au nanoclusters (NCs) that proper surface modification can selectively stabilize the desired Au0 core, conducive to the formation of size/structure-controlled Au NCs. Leveraging π-π enhanced ion-pairing interactions, ionic liquid (IL) cations are bonded to AuI -thiolate complexes. The hydrophobic-hydrophobic interactions between IL cations subsequently provide a good mechanism to prolong the size of the AuI -thiolate complexes, selectively producing small-sized Au NCs upon reduction. Through combined control over the structure and concentration of IL cations, pH and solvent polarity, we are able to produce atomically precise Au NCs with customizable size, atomic packing structure, and surface chemistry. This work also provides a facile means to integrate/synergize the materials functionalities of Au NCs and ILs, increasing their acceptance in diverse fields.

Thermodynamic study of interaction effects in aqueous solutions of purine and pyrimidine nucleobases ionic liquids at 298.15 K

We report herewith experimental density and osmotic pressure measurements for aqueous 1-ethyl-3-methylimidazolium ([Emim]), and 1-n-butyl-3-metylimidazolium ([Bmim]) based nucleobases ionic liquids [NBILs] at 298.15 K to gain thermodynamic understanding of NBIL – water mixtures. Molar volumes Vm, standard entropies S0 and lattice potential energies UPOT are reported at 298.15 K using density data of pure state NBILs. Large values of S0 and small UPOT explains the existence of NBILs in liquid state at ambient conditions. Experimental density data of aqueous NBIL solutions were used to obtain apparent, partial and electrostricted volumes from which electrostricted hydration numbers were obtained. It was found that observed hydration numbers are solely due to anion hydration as cation shows negligibly small hydration. Negative magnitudes of excess molar volumes confirm the hydrophobic nature of NBILs. Using experimental osmotic coefficients, water activity (aW), mean molal activity coefficient γ± of NBILs, excess Gibbs free energy change ΔGE due to mixing etc. were obtained and found that these aqueous systems show negative deviation from limiting law. At low concentration hydrophobic hydration is dominant whereas hydrophobic ion-association occurs at higher concentration revealed from minimum in osmotic coefficients. Application of McMillan–Mayer theory of solutions yielded osmotic second virial coefficients which are found to be negative indicating attractive type of ion-ion – ion-pair interactions.

Influence of crosslinking in phosphoric acid-doped poly(phenylene oxide) membranes on their proton exchange membrane properties

Phosphoric acid (PA)-doped membranes are promising electrolytes for high-temperature proton exchange membrane fuel cells (HT-PEMFCs). However, long-term durability issues have been an obstacle to their commercialization. Herein, we report a series of poly(phenylene oxide) (PPO)-based crosslinked membranes containing quaternary ammonium (QA) groups and exhibiting enhanced physicochemical stability and PA retention via ion-pair interactions between QA and PA. The degree of crosslinking in PPO by diamine crosslinker was controlled at 20, 30, and 40. The membranes were also crosslinked (degree = 20) using diamine crosslinkers with variable alkyl chain length (ethyl, butyl, and hexyl). All membranes exhibited sufficient thermal stability (5% weight loss temperatures (TD5%) = ∼230 °C) and oxidative stability (∼85% in the Fenton test). The PA uptake of the resulting membranes was controlled between 110 and 154% depending on their crosslinked structures. The membrane with the lowest degree of crosslinking (20) and shortest crosslinker exhibited the highest PA uptake and highest anhydrous proton conductivity (0.043 S/cm at 150 °C) in doped state. The proton conductivity was found to be significantly influenced by the PA uptake and crosslinked membrane structures. The highest PA retention of 89% was exhibited by the PA-doped membrane with the highest degree of crosslinking (40).

Harnessing Noncovalent Interactions for a Directed Evolution of a Six-Component Molecular Crystal.

Building up on weak orthogonal interactions in supramolecular chemistry, a six-component crystal is designed. Using five distinctly different noncovalent forces, namely, hydrogen bonding, halogen bonding, cation-π, anion-π, and ion-pair interactions, three six-component crystals were designed with crown-ether (I), thiourea (II), 2,3,5,6-tetrafluoro-1,4-dibromobenzene (III), lone-pair donating anion (IV), ammonium cation (V), and electron-rich aromatic ring (VI). The M06-2X functional which is highly suitable in describing other weak interactions fails for ion-pairs. Tuned range-separated (RS)-DFT calculations are found to be capable in describing the ionic interactions in molecular solids. Molecular dynamics simulations show that the predicted multicomponent crystals are stable at room temperature and reducing the ionic charges for the ion-pairs destabilizes them. The strong electrostatic interactions between the three ion-pairs, NH4+···ClO4-, NH4+···HSO4-, and NH4+···HCO3- is the primary driving force for the stabilization of the six-component crystal. Using a hybrid of strong and weak intermolecular interactions, one may generate exotic molecular complexity like n-component crystals.

A Versatile High-Temperature Electrochemical Pump for Hydrogen Separations

Hydrogen is an excellent energy carrier and can enable zero or near-zero emissions in transportation, stationary or remote power, and portable power applications. Over 95% of hydrogen is derived from reformed natural gas, steam cracking, and other fossil fuel processes that often cause complex mixtures requiring purification. Further, with an increasing demand for hydrogen delivery, there is a current search going on for converting and using natural gas pipelines to carry a blend of natural gas and hydrogen (up to 15% H2). By blending natural gas and H2, the growing demand for hydrogen delivery could be met, but this requires on-site hydrogen purification and compression. Electrochemical hydrogen pumps (ECHP), as a standalone device, could be a better solution for on-site hydrogen purification and compression, making a cost-effective and direct process.Most ECHP research focuses on membrane development and its relation to ECHP performance. Many of these studies use BASF fuel cell electrodes. The role of electrode ionomer binder on ECHP performance has not been investigated with rigor. This talk presents our work on investigating the influence of ionomer binders on ECHP performance at high temperatures. A newly developed PC-PBI membrane (50:50 QPPSf-PBI H3PO4) was used as HT-PEM in our ECHP. The newly developed PC-PBI HT-PEM overcomes the 180 °C temperature limitation of H3PO4 doped PBI by incorporating tethered cationic moieties into the polymer host that anchors the H3PO4 through ion-pair interactions. Further, this talk will reveal the advantage of employing phosphoric acid tethered polymer electrolyte by comparing it against a liquid phosphoric acid imbibed polymer electrolyte in electrode binders. The final part of this talk will present the high-temperature ECHP performance with new phosphonic acid functionalized polymer electrode binders under industrial relevant mixtures (e.g., syngas, cracking, and reformate mixtures). Our work has shown that the higher temperature operation of ECHP minimizes the impact from CO and performance is governed by H2 concentration in the mixtures.

Ion-Induced Phase Transfer of Cationic Dyes for Fluorescence-Based Electrolyte Sensing in Droplet Microfluidics.

Fluorescence-based sensing in droplet microfluidics requires small sample volumes, allows for high-throughput assays, and does not suffer from photobleaching as each flowing sensor is only scanned one time. In this paper, we report a selective and sensitive fluorescence-based ion-sensing methodology in droplet microfluidics using a T-junction PDMS chip. The oil stream is doped with sensor ingredients including an ionophore, a cation exchanger, and a permanently cationic fluorophore as the optical reporter. Electrolyte cations from the aqueous sample are extracted into oil segments and displace the cationic dyes into aqueous droplets. Laser-induced fluorescence of the two immiscible phases is collected alternately, which is in clear contrast to most other ion-selective optode configurations such as nanoparticle suspensions that rely on mixed optical signals of two phases. The cation exchanger, tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, is found to dramatically enhance the dye emission in the nonpolar sensing oil by preventing ion-pairing interactions and aggregations of the dye molecules, providing new insights into the mechanism of cationic dye-based ion sensors. The high dye brightness allows us to use low concentrations of sensing chemicals (e.g., 10 μM) in the oil and attain high sensitivity for detection of ions in an equal volume of sample. Using valinomycin as the ionophore and methylene blue as the dye, K+ is detected with a response time of ∼11 s, a logarithmic linear range of 10-5 to 10-2 M, a 20-fold total fluorescence response, >1000-fold selectivity against other electrolyte cations, and negligible cross-sensitivity toward the sample pH. The K+ concentration in untreated and undiluted whole blood and sweat samples is successfully determined by this microfluidic sensing method without optical interference from the droplet sample to the sensing oil. Detection of other ionic analytes can be achieved using the corresponding ionophores.

Competition of ion-pair during the transition from hydrogen bonding to electrostatic interaction on self-assembled monolayer

The competition of intermolecular interactions occurring on the cellular surface plays a vital role in governing biological recognition processes. Herein, the competition between ion-pair and electrostatic interaction on the surface of a reliable artificial membrane, 3-mercaptopropionic acid self-assembled monolayer (3-MPA SAM), was investigated using scanning electrochemical microscopy (secm). The electroactive agent ferrocenemethanol (FcCH2OH) with one hydroxyl group is adsorbed by terminal carboxyl groups of 3-MPA SAM via hydrogen bonding. Once FcCH2OH was oxidized into ferroceniummethanol (Fc+CH2OH) by applying an oxidative potential, the electrostatic interaction between Fc+CH2OH and the deprotonated carboxyl group of 3-MPA became the dominant intermolecular force in the reaction system accompanied by the breaking of hydrogen bonding. With the addition of perchlorate anion (ClO4−), noticeable competition between the ion-pair and electrostatic interaction was observed owing to the spontaneous pairing of Fc+CH2OH and ClO4−. The competitive strength of ion-pair could be enhanced by increasing ClO4− concentration or solution acidity. Compared with the other six anions, ClO4− has been proved to exhibit more effective competition with the electrostatic interaction, which might attribute to the differences in hydration energy and the pairing capacities with Fc+CH2OH. This work may contribute to comprehending the biological recognition on the cellular surface and deserve further investigation.

Ion-pair interactions between voltage-sensing domain IV and pore domain I regulate CaV1.1 gating

The voltage-gated calcium channel CaV1.1 belongs to the family of pseudo-heterotetrameric cation channels, which are built of four structurally and functionally distinct voltage-sensing domains (VSDs) arranged around a common channel pore. Upon depolarization, positive gating charges in the S4 helices of each VSD are moved across the membrane electric field, thus generating the conformational change that prompts channel opening. This sliding helix mechanism is aided by the transient formation of ion-pair interactions with countercharges located in the S2 and S3 helices within the VSDs. Recently, we identified a domain-specific ion-pair partner of R1 and R2 in VSD IV of CaV1.1 that stabilizes the activated state of this VSD and regulates the voltage dependence of current activation in a splicing-dependent manner. Structure modeling of the entire CaV1.1 in a membrane environment now revealed the participation in this process of an additional putative ion-pair partner (E216) located outside VSD IV, in the pore domain of the first repeat (IS5). This interdomain interaction is specific for CaV1.1 and CaV1.2 L-type calcium channels. Moreover, in CaV1.1 it is sensitive to insertion of the 19 amino acid peptide encoded by exon 29. Whole-cell patch-clamp recordings in dysgenic myotubes reconstituted with wild-type or E216 mutants of GFP-CaV1.1e (lacking exon 29) showed that charge neutralization (E216Q) or removal of the side chain (E216A) significantly shifted the voltage dependence of activation (V1/2) to more positive potentials, suggesting that E216 stabilizes the activated state. Insertion of exon 29 in the GFP-CaV1.1a splice variant strongly reduced the ionic interactions with R1 and R2 and caused a substantial right shift of V1/2, whereas no further shift of V1/2 was observed on substitution of E216 with A or Q. Together with our previous findings, these results demonstrate that inter- and intradomain ion-pair interactions cooperate in the molecular mechanism regulating VSD function and channel gating in CaV1.1.