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Cooperativity
Cooperativity is defined that when a ligand binds to a receptor with more than one binding site, the ligand causes a decrease or increase in affinity for the incoming ligands. If there is an increase in binding of the subsequent ligands, it is considered positive cooperativity. If a decrease of binding is demonstrated, then it is considered to be negative cooperativity. Examples of positive and negative cooperativity are hemoglobin 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 that $$\Delta G = \Delta H - T \Delta S \ $$. 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
 * $$\Delta G_S^\circ = \Delta G_A^\circ + \Delta G_B^\circ - \Delta G_{AB}^\circ $$
 * $$\Delta H_S^\circ = \Delta H_A^\circ + \Delta H_B^\circ - \Delta H_{AB}^\circ $$
 * $$\ T\Delta G_S^\circ = T\Delta H_A^\circ + T\Delta H_B^\circ - T\Delta S_{AB}^\circ $$

where:
 * $$\Delta G_A^\circ $$ = free energy of binding A
 * $$\Delta G_B^\circ $$ = free energy of binding B
 * $$\Delta G_S^\circ $$ = free energy of binding for A and B tethered
 * $$\Delta G_{AB}^\circ $$ = sum of the free energies of binding

It is considered that if $$\Delta G_S^\circ $$ than the sum of $$\Delta G_A^\circ $$ and $$\Delta G_B^\circ $$,it is positively cooperative. If $$\Delta G_S^\circ $$ is less, then it is negatively cooperative. Such interactions are not limited to receptor-lingand interactions; it is also studied 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). From this study, it is determined that entropy rather than enthalpy determines the binding energy of the system leading to negative cooperativity. The large change in entropy is 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.

Biological Application
Dendrimers in drug-delivery system is an example of various host-guest interactions. When using dendrimers, the interaction between the host (the dendrimer) and guest (the drug) 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 formation by increasing the solubility and bioavailability of the drug. In conjunction, dendrimers can also increase cellular uptake and targeting ability, and also decrease drug resistance.

It has been shown that solubility of various NSAIDs increases when it is encapsulated in PAMAM dendrimers. This study has shown that the increased 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 also to the increase in solubility would be the hydrophobic interaction between the aromatic groups in the drugs and the interior cavities of the dendrimer. When a drug is encapsulated within the dendrimer, its physical and physiological properties of the drug remain unaltered, including non-specificity and toxicity. However, when the dendrimer and the drug are covalently linked together, it can be used on specific tissue targeting and controlled release rates. Covalent conjugation of multiple drugs on the surface of a dendrimer however can pose the problem of insolubility.

This principle is also being studied for cancer treatment application. Several groups have encapsulated anti-cancer medications such as: Camptothecin, Methotrexate, and Doxorubicin. Results from these research has shown that dendrimers have increased aqueous solubility, slow down 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 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 bind, the indicator changes color or fluoresces. This technique is called 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. The analyte is added to the mixture and 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 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 blue 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 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 when it is bound to dsDNA than when it is unbound.

Conformational Switching
A crystalline solid has been traditionally viewed as a static entity where the movements of its atomic components are limited to its vibrational equilibrium. As seen by the transformation of graphite to diamond, solid to solid transformation can occur under physical or chemical pressure. It has been recently proposed that the transformation from one crystal arrangement to another occurs through a cooperative manner. Most of these studies have been focused in studying organic or metal-organic framework. In addition to studies of macromolecular crystalline transformation, there are also studies of single-crystal molecules can change their conformation in the presence of organic solvents. An organometallic complex has been shown to morph into various orientations depending on whether it is exposed to solvent vapors or not.