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A foldamer is a discrete chain molecule or oligomer that folds into a conformationally ordered state in solution. The structure of a foldamer is stabilized by multiple noncovalent interactions between nonadjacent monomers.

Foldamers find extremely useful applications as they provide insight into molecular self-assembly, molecular recognition, and host-guest chemistry. Currently foldamer molecules are defined by three different catagories: peptidomimetic foldamers, nucleotidomimetic foldamers, and abiotic foldamers. Peptidomimetic foldamers are synthetic molecules that mimic the structure of proteins, while nucleotidomimetic foldamers are based on the interactions in nucleic acids. Abiotic foldamers are stabilized by aromatic and charge-transfer interactions which are not generally found in nature. Foldamers are researched by a diverse collection of chemical, material and biophysical disciplines, with the main goal of designing oligomers with a predictable and reliable folding reactions.

=Foldamer Design=



It is important to note that foldamers are defined by a few characteristics. While foldamers can vary in oligomeric size, they are known to be stabilized by noncovalent, nonadjacent interactions. This excludes molecules like poly(isocyanates) (commonly known as (polyurethane)) and poly(prolines) as they fold into helicies reliably due to adjacent covalent interactions. , Foldamers have a dynamic folding reaction [unfolded → folded], in which large macroscopic folding is caused by solvophobic effects (hydrophobic collapse), while the final energy state of the folded foldamer is due to the noncovalent interactions. These interactions work cooperatively to form the most stable tertiary structure, as the completely folded and unfolded states are more stable than any partially folded state.

Prediction of Folding
Modern computing power offers the possibility of predicting the structure of a foldamer based on its primary sequence. This process involves dynamic simulations of the folding equilibria at the atomic level. An analysis of the stability of different folds under various thermodynamic and solvation conditions allows one to predict the most favorable conformation of the foldamer. This type of analysis may be applied to small proteins as well, however current computational technology is unable to simulate all but the shortest of sequences.

The folding pathway of a foldamer can be determined by measuring the variation from the experimentally determined favored structure under different thermodynamic and kinetic conditions. The change in structure is measured by calculating the root mean square deviation from the backbone atomal position of the favored structure. The structure of the foldamer under different conditions can be determined computationally and then verified experimentally. Changes in the temperature, solvent viscosity, pressure, pH, and salt concentration can all yield valuable information about the structure of the foldamer. Measuring the kinetics of folding as well as folding equilibria allow one to observe the effects of these different conditions on the foldamer structure.

Changes in solvent also often lead to a change in folding pattern. For example, a foldamer which begins its folding pathway with a hydrophobic collapse would have a very different folding pattern in a nonpolar solvent. This is due to the fact that different solvents stabilize different intermediates of the folding pathway as well as different final foldamer structures based on intermolecular noncovalent interactions.

Noncovalent Interactions
Noncovalent intermolecular interactions, albeit individually small, their summation alters chemical reactions in major ways. Listed below are common intermolecular forces that chemists have used to design foldamers.

- Hydrogen Bonding (especially with Peptide Bonds)

- Pi stacking

- Solvophobic effects, which lead to Hydrophobic collapse

- Van der Waals forces

- Electrostatic attraction

=Common Foldamer Designs= In each of the three designs described below, all three deviate from Hill's strict definition of a foldamer which excludes helical foldamers. In experimentation, however, helical foldamers are widely designed because helices are seen in biology and, out of the infinite number of possible foldamers to create, helices are rather predictable. The sections below are included as they are a quick summary of what foldamer designs are currently attractive to scientists.

Peptidomimetic
Peptidomimetic foldamers often break the previously mentioned definition of foldamers as they often form helical structure, yet, they are a major landmark of foldamer research due to their design and capabilities. , The largest groups of peptidomimetic consist of β – peptides, γ – peptides and δ – peptides, and the possible monomeric combinations. The amino acids of these peptides only differ by one (β), two (γ) or three (δ) methylene carbons, yet the structural changes were profound. These peptide sequences are highly studied as sequence control leads to reliable folding prediction. Additionally, with multiple methylene carbons between the carboxyl and amino termini of the flanking peptide bonds, Varying R group side chains can be designed. One example of the novelty of β-peptides can be seen in the findings of Reiser and coworkers. Using a heteroligopeptide consisting of α-amino acids and cis-β-aminocyclopropanecarboxulic acids (cis-β-ACCs) the found the formation of helical sequences in oligomers as short as seven residues and defined conformation in five residues; a quality unique to peptides containing cyclic β-amino acids.

For a comprehensive review, see Seebach, D.; Beck, A.K.; Bierbaum, D. J.; Chem. Biodiv., 2004, 1, 1111-1239.

Nucleotidomimetic
Nucleotidomimetics do not generally qualify as foldamers. Most are designed to mimic single DNA bases, nucleosides, or nucleotides in order to nonspecifically target DNA. These have several different medicinal uses including anti-cancer, anti-viral, and anti-fungal applications. However, some nucleotidomimetics do have foldamer properties. For example, antisense technology involves the target of a specific sequence of DNA or mRNA in the cell. These molecules are generally composed of several different nucleotide analogues attached together in a similar manner as DNA. These sorts of molecules do fold independently in solution in a similar fashion to single stranded RNA.

Abiotic
Abiotic foldamers are organic molecules designed to have a dynamic folding reaction, but do not have a peptide or nucleoside application. The applications are highly varied, but they all exploit one or a few known key intermolecular interactions, as optimized by their design. One example comes from the work of Johnathan Sessler, who developed oligopyrrole molecules that preferentially bind anions. He designed acyclic oligopyrrole molecules that preferentially bind anions, like chloride, through hydrogen bonding (see figure). The folding reaction is inacted in the presence of an anion, as the pyrrole groups have little conformational restriction otherwise. However, in the presence of a chloride, all 4 or 6 pyrroles direct their hydrogen bonds inwards from the electrostatic attraction of the chloride. The design of these simple foldamers originated from the synthesis of porphorins, a biological molecule used in metal binding.

For a review of Anion Controlled Foldamers see Juwarker, H.; Jeong, K-S. (2010). "Anion-controlled foldamers". Chem. Soc. Rev. 39: 3664-3674. doi:10.1039/b926162c

=References=