Host-guest chemistry
Encyclopedia
Supramolecular chemistry
Supramolecular chemistry refers to the area of chemistry beyond the molecules and focuses on the chemical systems made up of a discrete number of assembled molecular subunits or components...
, host-guest chemistry describes complexes
Complex (chemistry)
In chemistry, a coordination complex or metal complex, is an atom or ion , bonded to a surrounding array of molecules or anions, that are in turn known as ligands or complexing agents...
that are composed of two or more molecule
Molecule
A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...
s or ion
Ion
An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...
s that are held together in unique structural relationships by forces other than those of full covalent bond
Covalent bond
A covalent bond is a form of chemical bonding that is characterized by the sharing of pairs of electrons between atoms. The stable balance of attractive and repulsive forces between atoms when they share electrons is known as covalent bonding....
s. Host-guest chemistry encompasses the idea of molecular recognition and interactions through noncovalent bonding
Noncovalent bonding
A noncovalent bond is a type of chemical bond, typically between macromolecules, that does not involve the sharing of pairs of electrons, but rather involves more dispersed variations of electromagnetic interactions. The noncovalent bond is the dominant type of bond between supermolecules in...
. Noncovalent bonding is critical in maintaining the three-dimensional structure of large molecules, such as proteins and is involved in many biological processes in which large molecules bind specifically but transiently to one another. There are four commonly mentioned types of non-covalent interactions: hydrogen bond
Hydrogen bond
A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...
s, ionic bond
Ionic bond
An ionic bond is a type of chemical bond formed through an electrostatic attraction between two oppositely charged ions. Ionic bonds are formed between a cation, which is usually a metal, and an anion, which is usually a nonmetal. Pure ionic bonding cannot exist: all ionic compounds have some...
s, van der Waals forces, and hydrophobic interactions
Hydrophobic effect
The hydrophobic effect is the observed tendency of nonpolar substances to aggregate in aqueous solution and exclude water molecules. The name, literally meaning "water-fearing," describes the segregation and apparent repulsion between water and nonpolar substances...
.
Common host molecules
Commons host molecules are cyclodextrins, calixareneCalixarene
A calixarene is a macrocycle or cyclic oligomer based on a hydroxyalkylation product of a phenol and an aldehyde. The word calixarene is derived from calix or chalice because this type of molecule resembles a vase and from the word arene that refers to the aromatic building block...
s, cucurbituril
Cucurbituril
Cucurbiturils are methylene-linked macrocyclic molecules made of glycoluril [=C4H2N4O2=] monomers. The oxygen atoms are located along the edges of the band and are tilted inwards, forming a partly enclosed cavity...
s, porphyrin
Porphyrin
Porphyrins are a group of organic compounds, many naturally occurring. One of the best-known porphyrins is heme, the pigment in red blood cells; heme is a cofactor of the protein hemoglobin. Porphyrins are heterocyclic macrocycles composed of four modified pyrrole subunits interconnected at...
s , metallacrown
Metallacrown
thumb|300px|right|Figure showing the metallacrown analogy to the organic crown ether. Ligand substituents are omitted for clarity. a) 12-crown-4 b)12-MCFeN-4 c) 15-crown-5 d) 15-MCCuN-5...
s, crown ether
Crown ether
Crown ethers are cyclic chemical compounds that consist of a ring containing several ether groups. The most common crown ethers are oligomers of ethylene oxide, the repeating unit being ethyleneoxy, i.e., -CH2CH2O-. Important members of this series are the tetramer , the pentamer , and the hexamer...
s, zeolite
Zeolite
Zeolites are microporous, aluminosilicate minerals commonly used as commercial adsorbents. The term zeolite was originally coined in 1756 by Swedish mineralogist Axel Fredrik Cronstedt, who observed that upon rapidly heating the material stilbite, it produced large amounts of steam from water that...
s, cyclotriveratrylene
Cyclotriveratrylene
Cyclotriveratrylene is a macrocycle and used in host-guest chemistry as a molecular host . The compound can be synthesised from veratrole alcohol by addition of a suitable acid which can be perchloric acid in methanol or formic acid or sulfuric acid in acetic acid.An alternative is synthesis from...
s, cryptophane
Cryptophane
Cryptophanes are a class of organic supramolecular compounds studied and synthesized primarily for molecular encapsulation and recognition. One possible noteworthy application of cryptophanes is encapsulation and storage of hydrogen gas for potential use in fuel cell automobiles...
s and carcerand
Carcerand
A carcerand is a host molecule that completely entraps its guest so that it will not escape even at high temperatures. This type of molecule was first described by Donald J. Cram in 1985 and is derived from the Latin carcer, or prison...
s.
Host-guest chemistry is observed in inclusion compound
Inclusion compound
In host-guest chemistry an inclusion compound is a complex in which one chemical compound forms a cavity in which molecules of a second "guest" compound are located. The definition of inclusion compounds is very broad, extending to channels formed between molecules in a crystal lattice in which...
s, Intercalation
Intercalation (chemistry)
In chemistry, intercalation is the reversible inclusion of a molecule between two other molecules . Examples include DNA intercalation and graphite intercalation compounds.- DNA intercalation :...
compounds, clathrates and molecular tweezer
Molecular tweezer
Molecular tweezers, sometimes termed molecular clips, are noncyclic macro molecular complexes with open cavities capable of binding guests. The term "molecular tweezer" was first used by Howard J. Whitlock, but the class of hosts was developed and popularized by Steven C. Zimmerman in the mid-1980s...
s.
Thermodynamic Principles of Host-Guest Interactions
There is an equilibriumDynamic equilibrium
A dynamic equilibrium exists once a reversible reaction ceases to change its ratio of reactants/products, but substances move between the chemicals at an equal rate, meaning there is no net change. It is a particular example of a system in a steady state...
between the unbound state, in which the host and the guest are separate from each other, and the bound state, in which there is a structurally defined host-guest complex:
- H ="host" , G ="guest" , HG ="host-guest complex"
The "host" component can be considered the larger molecule, and it encompasses the smaller, "guest", molecule. In biological systems, the analogous terms of host and guest are commonly referred to as enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
and substrate
Substrate (biochemistry)
In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
respectively.
The thermodynamic benefits of host guest chemistry are derived from the idea that there is a lower overall Gibbs free energy
Gibbs free energy
In thermodynamics, the Gibbs free energy is a thermodynamic potential that measures the "useful" or process-initiating work obtainable from a thermodynamic system at a constant temperature and pressure...
due to the interaction between host and guest molecules. Chemists are exhaustively trying to measure the energy and thermodynamic properties of these non-covalent interactions found throughout supramolecular chemistry; and by doing so hope to gain further insight into the combinatorial outcome of these many, small, non-covalent forces that are used to generate an overall effect on the supramolecular structure.
In order to rationally and confidently design synthetic systems that perform specific functions and tasks, it is very important to understand the thermodynamics of binding between host and guest. Chemists are focusing on the energy exchange of different binding interactions and trying to develop scientific experiments to quantify the fundamental origins of these non-covalent interactions by utilizing various techniques such as NMR spectroscopy
NMR spectroscopy
Nuclear magnetic resonance spectroscopy, most commonly known as NMR spectroscopy, is a research technique that exploits the magnetic properties of certain atomic nuclei to determine physical and chemical properties of atoms or the molecules in which they are contained...
, Raman spectroscopy
Raman spectroscopy
Raman spectroscopy is a spectroscopic technique used to study vibrational, rotational, and other low-frequency modes in a system.It relies on inelastic scattering, or Raman scattering, of monochromatic light, usually from a laser in the visible, near infrared, or near ultraviolet range...
, isothermal titration calorimetry, surface tension, and UV-Vis Spectroscopy. The experimental data is quantified and explained through analysis of binding constants Ka, Gibbs free energy
Gibbs free energy
In thermodynamics, the Gibbs free energy is a thermodynamic potential that measures the "useful" or process-initiating work obtainable from a thermodynamic system at a constant temperature and pressure...
ΔGo, Enthalpy
Enthalpy
Enthalpy is a measure of the total energy of a thermodynamic system. It includes the internal energy, which is the energy required to create a system, and the amount of energy required to make room for it by displacing its environment and establishing its volume and pressure.Enthalpy is a...
ΔHo, and entropy
Entropy
Entropy is a thermodynamic property that can be used to determine the energy available for useful work in a thermodynamic process, such as in energy conversion devices, engines, or machines. Such devices can only be driven by convertible energy, and have a theoretical maximum efficiency when...
ΔSo.
Association and Dissociation constants
The association constant,
, is equal to the concentration of the Host-Guest complex divided by the product of the concentrations of the individual Host and Guest molecules when the system is in equilibrium.The equilibrium that has been established between the Host-Guest complex and free molecules can also be defined by a dissociation constant
Dissociation constant
In chemistry, biochemistry, and pharmacology, a dissociation constant is a specific type of equilibrium constant that measures the propensity of a larger object to separate reversibly into smaller components, as when a complex falls apart into its component molecules, or when a salt splits up into...
,
.
A Large
value can be equated to a small 
, both values indicate a strong complexation between host and guest molecules to form the host-guest complex.Gibbs Free Energy dependency on K
The Change in Gibbs Free Energy, ΔG, is a function of the equilibrium constant,
One can see that by knowing the association constant, you can solve for the Gibbs free energy of the reaction.
,One can also can see the dependency of Gibbs Free energy on the macroscopic terms of Enthalpy
Enthalpy
Enthalpy is a measure of the total energy of a thermodynamic system. It includes the internal energy, which is the energy required to create a system, and the amount of energy required to make room for it by displacing its environment and establishing its volume and pressure.Enthalpy is a...
, ΔH and Entropy
Entropy
Entropy is a thermodynamic property that can be used to determine the energy available for useful work in a thermodynamic process, such as in energy conversion devices, engines, or machines. Such devices can only be driven by convertible energy, and have a theoretical maximum efficiency when...
, ΔS.
Experimental Determination of [HG] using Kinetics
In order to determine the concentration of the
complex, one needs to write the equilibrium equation in terms that are able to be measured in the laboratory. Experimentally, one can determine the concentration of the host-guest complex, 
, as a function of the initial concentration of the guest molecules, 
.Their occurs a problem because our association constant, which one wants to relate to the Gibbs Free Energy of the system, is a function of the concentration of host,
and guest,
, molecules at equilibrium. Therefore, in order to be able to successfully determine the 
as a function of 
, one must make some assumptions. These assumptions are necessary because the scientist only known the initial concentrations of host and guest, 
and 
In order to overcome this obstacle, one can first make the alternative equilibrium approximation which states that the initial concentration of host molecules,
is equivalent to the concentration of both 
and 
; this is because sum of all 
is only found in 
and 
in terms of 
and 
:
Solving for
yields:
This can be substituted into the original equilibrium equation
In solving for
, one can determine that:
- At this point, we have gotten the concentration of
complex in terms of the initial concentration of host molecules, 
Another assumption that is made in the determination of
as a function of 
and 
is that by setting the initial concentration of the Guest molecules, 
, much greater than the initial concentration of Host molecules, 
; one can then say that:- because:
- then:
With this final substitution, one can solve for the concentration of the Host-Guest complex
as a function of the initial concentrations of the Host and Guest Molecules:
The final equation follows the form of the graph seen above. The plot above is called a binding isotherm which represents saturation kinetics and can be taken in 2 major parts.
At low concentrations of
, (1>>>
) the plot become linear as a function of 
.
becomes:
- This is represented in the plot by the increasing linear portion of the curve.
At high concentrations of
, 
then 
becomes independent of 
and the plot becomes a flat line again like seen in the very beginning of the curve.The plot becomes independent of
because when([G]o>>>1):
becomes:
- This function is independent of the
so thus the plot flattens out
This binding isotherm is one type of experimental data that can be analyzed and quantified by various spectroscopic imaging techniques; among others are Nuclear Magnetic Resonance
Nuclear magnetic resonance
Nuclear magnetic resonance is a physical phenomenon in which magnetic nuclei in a magnetic field absorb and re-emit electromagnetic radiation...
(NMR), Raman Spectroscopy
Raman spectroscopy
Raman spectroscopy is a spectroscopic technique used to study vibrational, rotational, and other low-frequency modes in a system.It relies on inelastic scattering, or Raman scattering, of monochromatic light, usually from a laser in the visible, near infrared, or near ultraviolet range...
, and isothermal titration calorimetry
Isothermal Titration Calorimetry
Isothermal titration calorimetry is a physical technique used to determine the thermodynamic parameters of interactions in solution. It is most often used to study the binding of small molecules to larger macromolecules .-Thermodynamic measurements:ITC is a quantitative technique that can...
. These spectroscopic methods can be help the scientist quantify the thermodynamic principles of host-guest chemistry.
Nuclear Magnetic Resonance
Nuclear magnetic resonanceNuclear magnetic resonance
Nuclear magnetic resonance is a physical phenomenon in which magnetic nuclei in a magnetic field absorb and re-emit electromagnetic radiation...
(NMR) is one of the most powerful spectroscopic techniques in analytical chemistry. It is an important tool for the studies of host-guest complexes, for elucidating the structures of the various complexes existing in the form of aggregates, ion pair or encapsulated systems.As the name suggests, NMR identifies the different nuclei
Atomic nucleus
The nucleus is the very dense region consisting of protons and neutrons at the center of an atom. It was discovered in 1911, as a result of Ernest Rutherford's interpretation of the famous 1909 Rutherford experiment performed by Hans Geiger and Ernest Marsden, under the direction of Rutherford. The...
in the molecules (most commonly, proton
Proton
The proton is a subatomic particle with the symbol or and a positive electric charge of 1 elementary charge. One or more protons are present in the nucleus of each atom, along with neutrons. The number of protons in each atom is its atomic number....
), by measuring their chemical shift
Chemical shift
In nuclear magnetic resonance spectroscopy, the chemical shift is the resonant frequency of a nucleus relative to a standard. Often the position and number of chemical shifts are diagnostic of the structure of a molecule...
. The binding activity of two molecules causes a considerable change in their electronic environments. This leads to a shift in the signals in the NMR spectrum, and this basic principle is made use of to study the phenomena of host-guest chemistry. The driving forces for host-guest binding are the various secondary interactions between molecules, such as hydrogen bonding and pi-pi interaction. Thus, NMR also serves as an important technique to establish the presence of these interactions in a host-guest complex.
Previous NMR studies have given useful information about the binding of different guest to hosts. Fox et al. calculated the hydrogen-bond interactions between pyridine molecules and poly(amido amine (PAMAM) dendrimer
Dendrimer
Dendrimers are repetitively branched molecules. The name comes from the Greek word "δένδρον" , which translates to "tree". Synonymous terms for dendrimer include arborols and cascade molecules. However, dendrimer is currently the internationally accepted term. A dendrimer is typically symmetric...
; on the basis of the chemical shift of the amine
Amine
Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...
and the amide
Amide
In chemistry, an amide is an organic compound that contains the functional group consisting of a carbonyl group linked to a nitrogen atom . The term refers both to a class of compounds and a functional group within those compounds. The term amide also refers to deprotonated form of ammonia or an...
groups. In a similar study, Xu et al. titrated carboxylate based G4 PAMAM dendrimer (the host) with various amine based drugs (the guests) and monitored the chemical shifts of the dendrimer. In conjunction with the 2D-NOESY NMR techniques, they were able to precisely locate the position of the drugs on the dendrimers and the effect of functionality on the binding affinity of the drugs. They found conclusive evidence to show that the cationic drug molecules attach on the surface of anionic dendrimers by electrostatic interactions, whereas an anionic drug localizes both in the core and the surface of the dendrimers, and that the strength of these interactions are dependent on the pKa
PKA
PKA, pKa, or other similar variations may stand for:* pKa, the symbol for the acid dissociation constant at logarithmic scale* Protein kinase A, a class of cAMP-dependent enzymes* Pi Kappa Alpha, the North-American social fraternity...
values of the molecules.
In a different study, Sun et al. studied the host-guest chemistry of ruthenium
Ruthenium
Ruthenium is a chemical element with symbol Ru and atomic number 44. It is a rare transition metal belonging to the platinum group of the periodic table. Like the other metals of the platinum group, ruthenium is inert to most chemicals. The Russian scientist Karl Ernst Claus discovered the element...
trisbipyridyl-viologen molecules with cucurbituril
Cucurbituril
Cucurbiturils are methylene-linked macrocyclic molecules made of glycoluril [=C4H2N4O2=] monomers. The oxygen atoms are located along the edges of the band and are tilted inwards, forming a partly enclosed cavity...
. Whilst monitoring the change in the chemical shifts of the pyridine
Pyridine
Pyridine is a basic heterocyclic organic compound with the chemical formula C5H5N. It is structurally related to benzene, with one C-H group replaced by a nitrogen atom...
protons on viologen
Viologen
Viologens are toxic bipyridinium derivatives of 4,4'-bipyridyl. The name is because this class of compounds is easily reduced to the radical mono cation, which is intensely blue coloured....
, they found that the binding modes for the 1:1 complexes are completely different for different cucurbituril molecules. In cucurbit[7]uril, only four aromatic protons per single bipyridyl ligand take part in the binding process, whilst all the aromatic protons of the ligand form a part of the complex when cucurbit[8]uril is used.
However, an important factor that has to be kept in mind while analyzing binding between the host and the guest is the time taken for data acquisition compared to the time for the binding event. In a lot of cases, the binding events are much faster than the time-scale of data acquisition, in which case the output is an averaged signal for the individual molecules and the complex. The NMR timescale is of the order of milliseconds, which in certain cases when the binding reaction is fast, limits the accuracy of the technique.
Raman spectroscopy
Raman spectroscopyRaman spectroscopy
Raman spectroscopy is a spectroscopic technique used to study vibrational, rotational, and other low-frequency modes in a system.It relies on inelastic scattering, or Raman scattering, of monochromatic light, usually from a laser in the visible, near infrared, or near ultraviolet range...
is a spectroscopic technique used in the study of molecules which exhibit a Raman scattering
Raman scattering
Raman scattering or the Raman effect is the inelastic scattering of a photon. It was discovered by Sir Chandrasekhara Venkata Raman and Kariamanickam Srinivasa Krishnan in liquids, and by Grigory Landsberg and Leonid Mandelstam in crystals....
effect when monochromatic light is incident on it. The basic requirement to get a Raman signal is that the incident light brings about an electronic transition in the chemical species from its ground state to a virtual energy state, which will emit a photon
Photon
In physics, a photon is an elementary particle, the quantum of the electromagnetic interaction and the basic unit of light and all other forms of electromagnetic radiation. It is also the force carrier for the electromagnetic force...
on returning to the ground state. The difference in energy between the absorbed and the emitted photon is unique for each chemical species depending on its electronic environment. Hence, the technique serves as an important tool for study of various binding events, as binding between molecules almost always results in a change in their electronic environment. However, what makes Raman spectroscopy a unique technique is that only transitions which are accompanied by a change in the polarization
Polarization
Polarization is a property of certain types of waves that describes the orientation of their oscillations. Electromagnetic waves, such as light, and gravitational waves exhibit polarization; acoustic waves in a gas or liquid do not have polarization because the direction of vibration and...
of the molecule are Raman active. The structural information derived from Raman spectra gives very specific information about the electronic configuration of the complex as compared to the individual host and guest molecules.
Solution phase Raman spectroscopy often results in a weak scattering cross-section. Therefore, recent advancements have been made to enhance the Raman signals, such as surface enhanced Raman spectroscopy
Surface Enhanced Raman Spectroscopy
Surface enhanced Raman spectroscopy or surface enhanced Raman scattering is a surface-sensitive technique that enhances Raman scattering by molecules adsorbed on rough metal surfaces...
, and Resonance Raman spectroscopy
Resonance Raman spectroscopy
Resonance Raman spectroscopy is a specialized implementation of the more general Raman spectroscopy.- Overview :As in Raman spectroscopy, RR spectroscopy provides information about the vibrations of molecules, and can also be used for identifying unknown substances. RR spectroscopy has found wide...
. Such techniques serve an additional purpose of quantifying the analyte-receptor binding events, giving a more detailed picture of the host-guest complexation phenomena where they actually take place; in solutions. In a recent breakthrough, Flood et al. determined the binding strength of tetrathiafulvalene (TTF) and cyclobis(paraquat-p-phenylene) using Raman spectroscopy as well as SERS
Surface Enhanced Raman Spectroscopy
Surface enhanced Raman spectroscopy or surface enhanced Raman scattering is a surface-sensitive technique that enhances Raman scattering by molecules adsorbed on rough metal surfaces...
. Prior work in this field was aimed at providing information on the bonding and the structure of the resulting complex, rather than quantitative measurements of the association strengths. The researchers had to use Resonance Raman spectroscopy in order to be able to get detectable signals from solutions with concentrations as low as 1 mM. In particular they correlated the intensity of the Raman bands with the geometry of the complex in the photo-excited state. Similar to UV-vis spectroscopy based titration; they calculated the binding constant by “Raman titration” and fitted the binding curves to 1:1 models, giving a
of -5.7±0.6 kcal/mol. The study is now providing a basis for similar studies involving charge transfer complexes in solutions.Isothermal titration calorimetry
Spectroscopic techniques give information about the binding constant
and Gibbs free energyGibbs free energy
In thermodynamics, the Gibbs free energy is a thermodynamic potential that measures the "useful" or process-initiating work obtainable from a thermodynamic system at a constant temperature and pressure...
,
. To get the complete set of thermodynamic parameters such as 
and 
, a Van’t Hoff analysis using the Van't Hoff equationVan't Hoff equation
The van 't Hoff equation also known as the Vukancic-Vukovic equation in chemical thermodynamics relates the change in temperature to the change in the equilibrium constant given the standard enthalpy change for the process...
would be required. However, recent advents in calorimetric techniques allows for the measurement of
and 
in a single experiment, thus enabling determination of all the thermodynamic parameters using the equation:
,provided that the experiment is carried out under isothermal conditions; hence the name isothermal calorimetry.
The procedure is similar to a conventional titration procedure wherein the host is added sequentially to the guest and the heat absorbed or evolved is measured, compared to a blank solution. The total heat released, Q corresponds to the association constant,
and 
by the equation:
Which can be simplified as
Where
= Initial molar concentration of the host
= Molar concentration of the guest
= volume of the vesselThe above equation can be solved by non-linear regression analysis to obtain the value of
and 
and subsequently 
and 
for that particular reaction.The advantages of isothermal titration calorimetry over the other commonly used techniques, apart from giving the entire set of thermodynamic parameters, are that it is more general and suited for a wide range of molecules. It is not necessary to have compounds with chromophores or UV-visible functional groups in order to monitor the binding process as the heat signal is a universal property of binding reactions. At the same time, the signal to noise ratio is pretty favorable which allows for more accurate determination of the binding constants, even under very dilute conditions.
A recent example of the use of this technique was for studying the binding affinity of the protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
membrane surrounding Escherichia coli
Escherichia coli
Escherichia coli is a Gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms . Most E. coli strains are harmless, but some serotypes can cause serious food poisoning in humans, and are occasionally responsible for product recalls...
to lipophilic cations used in drugs in various membrane mimetic environments. The motivation for the above study was that these membranes render the bacteria resistant to most quaternary ammonium cation
Quaternary ammonium cation
Quaternary ammonium cations, also known as quats, are positively charged polyatomic ions of the structure NR4+, R being an alkyl group or an aryl group. Unlike the ammonium ion and the primary, secondary, or tertiary ammonium cations, the quaternary ammonium cations are permanently charged,...
based compounds which have the anti-bacterial effects. Thus an understanding of the binding phenomena would enable design of effective antibiotics for E. coli. The researchers maintained a large excess of the ligand over the protein to allowing the binding reaction to go to completion. Using the above equations the researchers proceeded to calculate
, 
, 
and 
for each drug in different environments. The data indicated that the binding stoichiometry of the drug with the membrane was 1:1 with a micromolar value of 
. The negative values of 
, 
and 
indicated that the process was enthalpy driven with a value of 8-12 kcal/mol for each drug.UV-vis spectroscopy
UV-vis spectroscopy is one of the oldest and quickest methods of studying the binding activity of various molecules. The absorption of UV-light takes place at a time-scale of picoseconds, hence the individual signals from the species can be observed. At the same time, the intensity of absorption directly correlates with the concentration of the species, which enables easy calculation of the association constant. Most commonly, either the host or the guest is transparent to UV-light, whilst the other molecule is UV-sensitive. The change in the concentration of the UV-sensitive molecules is thus monitored and fitted onto a straight line using the Benesi-Hildebrand methodBenesi-Hildebrand method
The Benesi-Hildebrand method is a mathematical approach used in physical chemistry for the determination of the equilibrium constant K and stoichiometry of non-bonding interactions...
, from which the association constant can be directly calculated.
Additional information about the stoichiometry of the complexes is also obtained, as the Benesi-Hilderbrand method assumes a 1:1 stoichiometry between the host and the guest. The data will yield a straight line only if the complex formation also follows a similar 1:1 stoichiometry. A recent example of a similar calculation was done by Sun et al., wherein they titrated ruthenium trisbipyridyl-viologen molecules with cucurbit[7]urils and plotted the relative absorbance of the cucurbit molecules as a function of its total concentration at a specific wavelength. The data nicely fitted a 1:1 binding model with a binding constant of
.As an extension, one can fit the data to different stoichiometries to understand the kinetics of the binding events between the host and the guest. made use of this corollary to slightly modify the conventional Benesi-Hilderbrand plot to get the order of the complexation reaction between barium-containing crown ether bridged chiral heterotrinuclear salen Zn(II) complex
(host) with various guests imidazoles and amino acid methyl esters, along with the other parameters. They titrated a fixed concentration of the zinc complex with varying amounts of the imidazoles and methyl esters whilst monitoring the changes in the absorbance of the pi to pi* transition band at 368 nm. The data fit a model in which the ratio of guest to host of 2 in the complex. They further carried these experiments at various temperatures which enabled them to calculate the various thermodynamic parameters using the Van't Hoff equationVan't Hoff equation
The van 't Hoff equation also known as the Vukancic-Vukovic equation in chemical thermodynamics relates the change in temperature to the change in the equilibrium constant given the standard enthalpy change for the process...
.
Cooperativity
Cooperativity is defined to be when a ligand binds to a receptor with more than one binding site, the ligand causes a decrease or increase in affinity for incoming ligands. If there is an increase in binding of the subsequent ligands, it is considered positive cooperativity. If a decrease of binding is observed, then it is negative cooperativity. Examples of positive and negative cooperativity are hemoglobinHemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
and aspartate receptor, respectively.
In recent years, the thermodynamic properties of cooperativity have been studied in order to define mathematical parameters that distinguish positive or negative cooperativity. The traditional Gibbs free energy equation states:
. However, to quantify cooperativity in a host-guest system, the binding energy needs to be considered. The schematic on the right shows the binding of A, binding of B, positive cooperative binding of A-B, and lastly, negative cooperative binding of A-B. Therefore, an alternate form of the Gibbs free energy equation would be
where:
= free energy of binding A
= free energy of binding B
= free energy of binding for A and B tethered
= sum of the free energies of bindingIt is considered that if
more than the sum of 
and 
,it is positively cooperative. If 
is less, then it is negatively cooperative.Host-guest chemistry is not limited to receptor-lingand interactions. It is also demonstrated in ion-pairing systems. In recent years, such interactions are studied in an aqueous media utilizing synthetic organometallic hosts and organic guest molecules. For example, a poly-cationic receptor containing copper (the host) is coordinated with molecules such as tetracarboxylates, tricarballate, aspartate, and acetate (the guests). This study illustrates that entropy
Entropy
Entropy is a thermodynamic property that can be used to determine the energy available for useful work in a thermodynamic process, such as in energy conversion devices, engines, or machines. Such devices can only be driven by convertible energy, and have a theoretical maximum efficiency when...
rather than enthalpy
Enthalpy
Enthalpy is a measure of the total energy of a thermodynamic system. It includes the internal energy, which is the energy required to create a system, and the amount of energy required to make room for it by displacing its environment and establishing its volume and pressure.Enthalpy is a...
determines the binding energy of the system leading to negative cooperativity. The large change in entropy originates from the displacement of solvent molecules surrounding the ligand and the receptor. When multiple acetates bind to the receptor, it releases more water molecules to the environment than a tetracarboxylate. This led to a decrease in free energy implying that the system is cooperating negatively. In a similar study, utilizing guanidinium and Cu(II) and polycarboxylate guests, it is demonstrated that positive cooperatively is largely determined by enthalpy. In addition to thermodynamic studies, host-guest chemistry also has biological applications.
Biological Application
Dendrimers in drug-delivery system is an example of various host-guest interactions. The interaction between the host and the guest, the dendrimerDendrimer
Dendrimers are repetitively branched molecules. The name comes from the Greek word "δένδρον" , which translates to "tree". Synonymous terms for dendrimer include arborols and cascade molecules. However, dendrimer is currently the internationally accepted term. A dendrimer is typically symmetric...
and the drug, respectively, can either be hydrophobic or covalent. Hydrophobic interaction between the host and the guest is considered “encapsulated,” while covalent interactions are considered to be conjugated. The utilization of dendrimers in medicine has shown to improve drug delivery by increasing the solubility and bioavailability of the drug. In conjunction, dendrimers can increase both cellular uptake and targeting ability, and decrease drug resistance.
The solubility of various NSAIDs increases when it is encapsulated in PAMAM dendrimers. This study shows the enhancement of NSAID solubility is due to the electrostatic interactions between the surface amine groups in PAMAM and the carboxyl groups found in NSAIDs. Contributing to the increase in solubility are the hydrophobic interactions between the aromatic groups in the drugs and the interior cavities of the dendrimer. When a drug is encapsulated within a dendrimer, its physical and physiological properties remains unaltered, including non-specificity and toxicity. However, when the dendrimer and the drug are covalently linked together, it can be used for specific tissue targeting and controlled release rates. Covalent conjugation of multiple drugs on dendrimer surfaces can pose a problem of insolubility.
This principle is also being studied for cancer treatment application. Several groups have encapsulated anti-cancer medications such as: Camptothecin
Camptothecin
Camptothecin is a cytotoxic quinoline alkaloid which inhibits the DNA enzyme topoisomerase I . It was discovered in 1966 by M. E. Wall and M. C. Wani in systematic screening of natural products for anticancer drugs. It was isolated from the bark and stem of Camptotheca acuminata , a tree native to...
, Methotrexate
Methotrexate
Methotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...
, and Doxorubicin
Doxorubicin
Doxorubicin INN is a drug used in cancer chemotherapy. It is an anthracycline antibiotic, closely related to the natural product daunomycin, and like all anthracyclines, it works by intercalating DNA....
. Results from these research has shown that dendrimers have increased aqueous solubility, slowed release rate, and possibly control cytotoxicity of the drugs. Cisplatin has been conjugated to PAMAM dendrimers that resulted in the same pharmacological results as listed above, but the conjugation also helped in accumulating cisplatin
Cisplatin
Cisplatin, cisplatinum, or cis-diamminedichloroplatinum is a chemotherapy drug. It is used to treat various types of cancers, including sarcomas, some carcinomas , lymphomas, and germ cell tumors...
in solid tumors in intravenous administration.
Sensing
Traditionally, chemical sensing has been approached with a system that contains a covalently bound indicator to a receptor though a linker. Once the analyte binds, the indicator changes color or fluoresces. This technique is called the indicator-spacer-receptor approach (ISR). In contrast to ISR, Indicator-Displacement Assay (IDA) utilizes a non-covalent interaction between a receptor (the host), indicator, and an analyte (the guest). Similar to ISR, IDA also utilizes colorimetric (C-IDA) and fluorescence (F-IDA) indicators. In an IDA assay, a receptor is incubated with the indicator. When the analyte is added to the mixture, the indicator is released to the environment. Once the indicator is released it either changes color (C-IDA) or fluoresces (F-IDA).IDA offers several advantages versus the traditional ISR chemical sensing approach. First, it does not require the indicator to be covalently bound to the receptor. Secondly, since there is no covalent bond, various indicators can be used with the same receptor. Lastly, the media in which the assay may be used is diverse.
Chemical sensing techniques such as C-IDA have biological implications. For example, protamine
Protamine
Protamines are small, arginine-rich, nuclear proteins that replace histones late in the haploid phase of spermatogenesis and are believed essential for sperm head condensation and DNA stabilization. They may allow for denser packaging of DNA in spermatozoon than histones, but they must be...
is a coagulant that is routinely administered after cardiopulmonary surgery that counter acts the anti-coagulant activity of herapin. In order to quantify the protamine in plasma samples, a colorimetric displacement assay is used. Azure A dye is purple when it is unbound, but when it is bound to herapin, it shows a blue color. The binding between Azure A and herapin is weak and reversible. This allows protamine to displace Azure A. Once the dye is liberated it displays a purple color. The degree to which the dye is displaced is proportional to the amount of protamine in the plasma.
F-IDA has been used by Kwalczykowski and co-workers to monitor the activities of helicase
Helicase
Helicases are a class of enzymes vital to all living organisms. They are motor proteins that move directionally along a nucleic acid phosphodiester backbone, separating two annealed nucleic acid strands using energy derived from ATP hydrolysis.-Function:Many cellular processes Helicases are a...
in E.coli. In this study they used thiazole orange as the indicator. The helicase unwinds the dsDNA to make ssDNA. The fluorescence intensity of thiazole orange has a greater affinity for dsDNA than ssDNA and its fluorescence intensity increases when it is bound to dsDNA than when it is unbound.