Synthetic ion channels
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Synthetic ion channels are ''de novo'' chemical compounds that insert into
lipid bilayer The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many vir ...
s, form pores, and allow
ion An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conven ...
s to flow from one side to the other. They are man-made analogues of natural
ion channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of io ...
s, and are thus also known as artificial ion channels. Compared to biological channels, they usually allow fluxes of similar magnitude but are # minuscule in size (less than 5k
Dalton Dalton may refer to: Science * Dalton (crater), a lunar crater * Dalton (program), chemistry software * Dalton (unit) (Da), the atomic mass unit * John Dalton, chemist, physicist and meteorologist Entertainment * Dalton (Buffyverse), minor cha ...
vs. > 100k Dalton), # diverse in molecular architecture, and # may rely on diverse supramolecular interactions to pre-form the active, conducting structures. Synthetic channels, like natural channels, are usually characterized by a combination of
single-molecule A single-molecule experiment is an experiment that investigates the properties of individual molecules. Single-molecule studies may be contrasted with measurements on an ensemble or bulk collection of molecules, where the individual behavior of mo ...
(e.g., voltage-clamp of planar bilayers) and ensemble techniques (flux in
vesicles Vesicle may refer to: ; In cellular biology or chemistry * Vesicle (biology and chemistry), a supramolecular assembly of lipid molecules, like a cell membrane * Synaptic vesicle ; In human embryology * Vesicle (embryology), bulge-like features o ...
). The study of synthetic ion channels can potentially lead to new single-molecule sensing technologies as well as new therapeutics.


History

While semi-synthetic ion channels, often based on modified peptidic channels like
gramicidin Gramicidin, also called gramicidin D, is a mix of ionophoric antibiotics, gramicidin A, B and C, which make up about 80%, 5%, and 15% of the mix, respectively. Each has 2 isoforms, so the mix has 6 different types of gramicidin molecules. They c ...
, had been prepared since the 1970s, the first attempt to prepare a synthetic ion channel was made in 1982 using a substituted β-
cyclodextrin Cyclodextrins are a family of cyclic oligosaccharides, consisting of a macrocyclic ring of glucose subunits joined by α-1,4 glycosidic bonds. Cyclodextrins are produced from starch by enzymatic conversion. They are used in food, pharmaceutical, ...
. Inspired by gramicidin, this molecule was designed to be a barrel-shaped entity spanning a single leaflet of a bilayer membrane, becoming "active" only when two molecules in opposite leaflets come together in an end-to-end fashion. While the compound does induce ion-fluxes in vesicles, the data does not unambiguously show ''channel'' formation (as opposed to other transport mechanisms; see
Mechanism Mechanism may refer to: *Mechanism (engineering), rigid bodies connected by joints in order to accomplish a desired force and/or motion transmission *Mechanism (biology), explaining how a feature is created *Mechanism (philosophy), a theory that a ...
). Na+ transport by such channels was first reported by two groups of investigators in 1989–1990.G. W. Gokel, I. A. Carasel ''Biologically active, synthetic ion transporters'' Chem. Soc. Rev., 2007, 36, 378. With the adoption of
voltage clamp The voltage clamp is an experimental method used by electrophysiologists to measure the ion currents through the membranes of excitable cells, such as neurons, while holding the membrane voltage at a set level. A basic voltage clamp will iterativ ...
technique to synthetic channel research in the early 1990s, researchers were able to observe quantized electrical activities from synthetic molecules, often considered the signature evidence for ion channels. This led to a sustained increase in research activity over the next two decades. In 2009, over 25
peer-review Peer review is the evaluation of work by one or more people with similar competencies as the producers of the work (peers). It functions as a form of self-regulation by qualified members of a profession within the relevant field. Peer review ...
ed papers were published on the topic, and a series of comprehensive reviews are available.


Characterization and mechanisms

Passive transport Passive transport is a type of membrane transport that does not require energy to move substances across cell membranes. Instead of using cellular energy, like active transport, passive transport relies on the second law of thermodynamics to d ...
of ions across a membrane can take place by three main mechanisms: by ferrying, through defects in a disrupted membrane, or through a defined trajectory; these corresponds to ''
ionophore In chemistry, an ionophore () is a chemical species that reversibly binds ions. Many ionophores are lipid-soluble entities that transport ions across the cell membrane. Ionophores catalyze ion transport across hydrophobic membranes, such as liq ...
'', ''
detergent A detergent is a surfactant or a mixture of surfactants with cleansing properties when in dilute solutions. There are a large variety of detergents, a common family being the alkylbenzene sulfonates, which are soap-like compounds that are more ...
'', and ''
ion channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of io ...
'' transporters. While synthetic ion channel research attempts to prepare compounds that show conductance ''via'' a defined path, the elucidation of mechanism is difficult and seldom unambiguous. The two main methods of characterization both have their drawbacks, and as a consequence, often function is defined but mechanism presumed.


Ensemble, vesicle-based time course

One line of evidence for ion transport comes from
macroscopic The macroscopic scale is the length scale on which objects or phenomena are large enough to be visible with the naked eye, without magnifying optical instruments. It is the opposite of microscopic. Overview When applied to physical phenomena an ...
examination of
statistical ensemble In physics, specifically statistical mechanics, an ensemble (also statistical ensemble) is an idealization consisting of a large number of virtual copies (sometimes infinitely many) of a system, considered all at once, each of which represents a ...
s. All these techniques use intact vesicles with an entrapped volume, with ion channel activities reported by different
spectroscopic Spectroscopy is the field of study that measures and interprets the electromagnetic spectra that result from the interaction between electromagnetic radiation and matter as a function of the wavelength or frequency of the radiation. Matter wav ...
methods. In a typical case, a
dye A dye is a colored substance that chemically bonds to the substrate to which it is being applied. This distinguishes dyes from pigments which do not chemically bind to the material they color. Dye is generally applied in an aqueous solution an ...
is entrapped within the population of vesicles. This dye is selected to be respond colorimetrically or fluorometrically to the presence of an ion; this ion is typically absent from the inside of the vesicle but present in the outside. Without an ion transporter, the lipid bilayer as a kinetic barrier to block ion flux, and the dye remains "dark" indefinitely. As an ion transporter allows ions on the outside to diffuse in, its addition will affect the color/fluorescence property of the dye. By macroscopically monitoring the dye's properties over time, and controlling outside factors, the ability of a compound to act as an ion transporter can be measured. Observing ion transport, however, does not pin down ion channel as the mechanism. Any class of transporter can lead to the same observation, and additional corroborating evidence is usually required. Sophisticated experiments intended to probe selectivity, gating, and other channel parameters have been developed over the past two decades and recently summarized.


Vesicle assay variations


Stochastic, planar bilayer-based current traces

An alternative to the ensemble-based method described above is the voltage-clamp experiment. In a voltage-clamp experiment, two compartments of
electrolyte An electrolyte is a medium containing ions that is electrically conducting through the movement of those ions, but not conducting electrons. This includes most soluble salts, acids, and bases dissolved in a polar solvent, such as water. Upon dis ...
are divided by an aperture, usually between 5-250 micrometres in diameter. A lipid bilayer is painted across this aperture, thus electrically separating the compartments; the molecular nature can be ascertained by measuring its
capacitance Capacitance is the capability of a material object or device to store electric charge. It is measured by the change in charge in response to a difference in electric potential, expressed as the ratio of those quantities. Commonly recognized are ...
. Upon the addition of an (ideal) ion channel, a defined path between the two compartments is formed. Through this pore, ions flow down the potential and electrochemical gradient rapidly (>106/second), the maximum flux limited by the geometry and dimensions of the pore. At some later instant the pore may close or collapse, whereupon the current returns to zero. This open-state current, originating and amplified from a single-molecule event, is typically on the order of pA to nA, with time-resolution of approx. millisecond. Ideal or close-to-ideal events is termed "''square-tops''" in the literature, and have been considered as signature for a channel-based mechanism. It is notable that the events observed at this scale are truly
stochastic Stochastic (, ) refers to the property of being well described by a random probability distribution. Although stochasticity and randomness are distinct in that the former refers to a modeling approach and the latter refers to phenomena themselv ...
- that is, they are the result of random molecular collision and conformation changes. As the membrane area is much larger than that of a pore, multiple copies may open and close independently of one another, giving rise to the staircase like appearance (Panel C in figure); these ideal events are often modelled as
Markov process A Markov chain or Markov process is a stochastic model describing a sequence of possible events in which the probability of each event depends only on the state attained in the previous event. Informally, this may be thought of as, "What happe ...
es. By using the ''activity grid notation'', synthetic ion channels studied with the voltage-clamp method during the period 1982-2010 have been critically reviewed. While the ideal traces are most frequently analyzed and reported in the literature, many records are decidedly non-ideal, with a subset was shown to be fractal. Developing methods for analyzing these non-ideal traces and clarifying their relationship to transport mechanism is an area of contemporary research.


Examples

A diverse and large pool of synthetic molecules have been reported to act as ion transporters in lipid membranes. A selection is described here to demonstrate the breadth of feasible ''structures'' and attainable ''functions''. Comprehensive reviews for the literature up to 2010 are available in a tripartite series.


By chemical structure

Most (but not all; see minimalist channels) synthetic channels have chemical structures substantially larger than typical small molecules (molecular weights ~1-5kDa). This originates from the need to be
amphiphilic An amphiphile (from the Greek αμφις amphis, both, and φιλíα philia, love, friendship), or amphipath, is a chemical compound possessing both hydrophilic (''water-loving'', polar) and lipophilic (''fat-loving'') properties. Such a compoun ...
, that is, have both sufficient hydrophobic portions to allow partitioning into lipid bilayer, as well as polar or charged "headgroups" to assert a defined orientation and geometry with respect to the membrane.


Macrocycles-based


=Crown ethers-based

=


=Calixarene-based

= Ion channels containing
calixarene A calixarene is a macrocycle or cyclic oligomer based on a methylene-linked phenols. With hydrophobic cavities that can hold smaller molecules or ions, calixarenes belong to the class of cavitands known in host–guest chemistry. Nomenclature Cal ...
s of ring size 3 and 4 have both been reported. For calix rene, two conformations are accessible, and examples of both ''1,3-alt'' and ''cone'' conformation have been developed.


=Cyclodextrin-based

= The first synthetic ion channel was constructed by partial substitution on the primary rim of β-
cyclodextrin Cyclodextrins are a family of cyclic oligosaccharides, consisting of a macrocyclic ring of glucose subunits joined by α-1,4 glycosidic bonds. Cyclodextrins are produced from starch by enzymatic conversion. They are used in food, pharmaceutical, ...
. Other substituted β-cyclodextrins have since been reported, including thiol-modified cyclodextrins, an anion-selective oligobutylene channel, and various poly-ethyleneoxide linked starburst oligomers. Structure-activity relationships for a large suite of cyclodextrin "half-channels" prepared by "click"-chemistry has been recently reported.


Rigid rods


Peptide-based

Alternating D/L peptide macrocycles are known to self-aggregate into nanotubes, and the resulting nanotubes have been shown to act as ion channels in lipid membranes. Other architectures use peptide helices as a scaffold to attach other functionalities, such as crown ethers of different sizes. The property of these peptide-crown channels depend strongly on the identity of the capping end-groups.


Minimalist channels


Miscellaneous


=G-quartet based channels

=


=Metal-organic channels

=


Hybrid bio-channels

Semi-synthetic bio-hybrid channels constructed by modifications of natural ion channels had been constructed. Leveraging modern synthetic
organic chemistry Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms.Clayden, J.; ...
, these allows pinpoint modifications of existing structures to either elucidate their transport mechanisms or to graft on new functionalities.
Gramicidin Gramicidin, also called gramicidin D, is a mix of ionophoric antibiotics, gramicidin A, B and C, which make up about 80%, 5%, and 15% of the mix, respectively. Each has 2 isoforms, so the mix has 6 different types of gramicidin molecules. They c ...
and
alamethicin Alamethicin is a channel-forming peptide antibiotic, produced by the fungus ''Trichoderma viride''. It belongs to peptaibol peptides which contain the non-proteinogenic amino acid residue Aib (2-aminoisobutyric acid). This residue strongly indu ...
had been popular starting points for selective modifications. The above diagram illustrates one example, where a crown-ether was fixed across the mouth of the ion-passing portal. This channel shows discrete conductance but different ion selectivity than
wild type The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, "m ...
gramicidin in voltage-clamp experiments. While modification of large protein channels using
mutagenesis Mutagenesis () is a process by which the genetic information of an organism is changed by the production of a mutation. It may occur spontaneously in nature, or as a result of exposure to mutagens. It can also be achieved experimentally using la ...
are generally considered out of the scope of ''synthetic'' channels, the demarcation is not sharp, as supramolecular or covalent bonding of cyclodextrins to alpha-hemolysin demonstrates.


By transport characteristics

An ion channel can be characterized by its ''opening characteristics'', ''ion selectivity'', and ''control of flux'' (gating). Many synthetic ion channels show unique properties in one or more of these aspects.


Opening characteristics

An "ion-channel forming" molecule can often show multiple types of conductance activities in planar bilayer membranes. Each of these modes of action can be characterized by their * open duration (sub-ms---hours), related to whether the active structure is kinetically labile, * unit conductance (pS---nS), related to the geometry of the active structure, and * open probability, a fraction related to the thermodynamic stability of that active structure relative to inactive forms. These ''events'' are not necessarily uniform throughout their durations, and as a result a variety of shapes of conducting traces are possible.


Ion selectivity

The majority of synthetic ion channels follow an Eisenman I sequence (Cs+ > Rb+ > K+ > Na+ >> Li+) in their selectivity for
alkali metal The alkali metals consist of the chemical elements lithium (Li), sodium (Na), potassium (K),The symbols Na and K for sodium and potassium are derived from their Latin names, ''natrium'' and ''kalium''; these are still the origins of the names ...
cations, suggesting that the origin of the selectivity is governed by the difference in energy required to remove water from a fully hydrated cation. A few synthetic channels show other patterns of ion selectivity, and only a single instance in which a synthetic channel following the opposite selectivity sequence (Eisenman XI; Cs+ < Rb+ < K+ < Na+ << Li+) had been reported.


Gating


=Voltage response

= Most synthetic channels are
Ohm Ohm (symbol Ω) is a unit of electrical resistance named after Georg Ohm. Ohm or OHM may also refer to: People * Georg Ohm (1789–1854), German physicist and namesake of the term ''ohm'' * Germán Ohm (born 1936), Mexican boxer * Jörg Ohm (b ...
ic in conductance, that is, the current passed (both individually and as an ensemble) is proportional to the potential across the membrane. Some rare channels, however, show current-voltage characteristics that is non-linear. Specifically, two different types of non-Ohmic conductance are known: # a ''rectifying'' behaviour, where current passes depends on the sign of the applied potential, and # a ''exponential potential dependence'', where the current passed scales exponentially with the applied potential. The former requires asymmetry with respect to the mid-plane of the lipid bilayer, and is realized often by introducing an overall molecular dipole. The latter, demonstrated in natural channels such as
alamethicin Alamethicin is a channel-forming peptide antibiotic, produced by the fungus ''Trichoderma viride''. It belongs to peptaibol peptides which contain the non-proteinogenic amino acid residue Aib (2-aminoisobutyric acid). This residue strongly indu ...
, is rarely encountered in synthetic ion channels. They may be related to lipid ion channels, but to date their mechanism remains elusive.


=Ligand response

= Certain synthetic ion channels have conductances that can be modulated by additional of external chemicals. Both up-modulation (channels are turned on by ligand) and down-modulation (channels are turned off by ligands) are known: different mechanisms, including formation of supramolecular aggregates, as well as inter- and intramolecular blockage.


=Others

= Regulatory elements that responds to other signals are known; examples include photomodulated conductances as well as "thermal switches" constructed by isomerization of the
carbamate In organic chemistry, a carbamate is a category of organic compounds with the general formula and structure , which are formally derived from carbamic acid (). The term includes organic compounds (e.g., the ester ethyl carbamate), formally o ...
group. To date, no mechanosensitive synthetic ion channels have been reported.


See also

*
Nanotechnology Nanotechnology, also shortened to nanotech, is the use of matter on an atomic, molecular, and supramolecular scale for industrial purposes. The earliest, widespread description of nanotechnology referred to the particular technological goal o ...
*
Supramolecular chemistry Supramolecular chemistry refers to the branch of chemistry concerning chemical systems composed of a discrete number of molecules. The strength of the forces responsible for spatial organization of the system range from weak intermolecular forces, ...
*
Macrocycle Macrocycles are often described as molecules and ions containing a ring of twelve or more atoms. Classical examples include the crown ethers, calixarenes, porphyrins, and cyclodextrins. Macrocycles describe a large, mature area of chemistry. ...
s *
Amphiphile An amphiphile (from the Greek αμφις amphis, both, and φιλíα philia, love, friendship), or amphipath, is a chemical compound possessing both hydrophilic (''water-loving'', polar) and lipophilic (''fat-loving'') properties. Such a compoun ...
*
Ionophore In chemistry, an ionophore () is a chemical species that reversibly binds ions. Many ionophores are lipid-soluble entities that transport ions across the cell membrane. Ionophores catalyze ion transport across hydrophobic membranes, such as liq ...
*
Membrane biophysics Membrane biology is the study of the biological and physiochemical characteristics of membranes, with applications in the study of cellular physiology. Membrane bioelectrical impulses are described by the Hodgkin cycle. Biophysics Membrane bioph ...
*
Membrane protein Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location. Integral membrane proteins are a permanent part of a cell membrane ...
*
Voltage-gated ion channel Voltage-gated ion channels are a class of transmembrane proteins that form ion channels that are activated by changes in the electrical membrane potential near the channel. The membrane potential alters the conformation of the channel proteins, ...
*
Pore-forming toxin Pore-forming proteins (PFTs, also known as pore-forming toxins) are usually produced by bacteria, and include a number of protein exotoxins but may also be produced by other organisms such as apple snails that produce perivitellin-2 or earthwor ...
*
Antimicrobial peptides Antimicrobial peptides (AMPs), also called host defence peptides (HDPs) are part of the innate immune response found among all classes of life. Fundamental differences exist between prokaryotic and eukaryotic cells that may represent targets for a ...
*
Electrophysiology Electrophysiology (from Greek , ''ēlektron'', "amber" etymology of "electron"">Electron#Etymology">etymology of "electron" , ''physis'', "nature, origin"; and , '' -logia'') is the branch of physiology that studies the electrical properties of b ...


References

{{DEFAULTSORT:Synthetic Ion Channels Supramolecular chemistry Molecular biology Nanotechnology Ion channels Electrophysiology Synthetic biology