In chemistry, a foldamer is a discrete chain molecule (

oligomer In chemistry and biochemistry, an oligomer () is a molecule that consists of a few repeating units which could be derived, actually or conceptually, from smaller molecules, monomers.Quote: ''Oligomer molecule: A molecule of intermediate relat ...

) that

folds Benjamin Scott Folds (born September 12, 1966) is an American singer-songwriter, musician, and composer, who is the first artistic advisor to the National Symphony Orchestra at the John F. Kennedy Center for the Performing Arts, Kennedy Center in ...

into a conformationally ordered state in solution. They are artificial molecules that mimic the ability of

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...

nucleic acid Nucleic acids are biopolymers, macromolecules, essential to all known forms of life. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main ...

s, and

polysaccharide Polysaccharides (), or polycarbohydrates, are the most abundant carbohydrates found in food. They are long chain polymeric carbohydrates composed of monosaccharide units bound together by glycosidic linkages. This carbohydrate can react with ...

s to fold into well-defined conformations, such as

α-helices The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues earli ...

and β-sheets. The structure of a foldamer is stabilized by noncovalent interactions between nonadjacent

monomers In chemistry, a monomer ( ; ''mono-'', "one" + '' -mer'', "part") is a molecule that can react together with other monomer molecules to form a larger polymer chain or three-dimensional network in a process called polymerization. Classification ...

. Foldamers are studied with the main goal of designing large molecules with predictable structures. The study of foldamers is related to the themes of

molecular self-assembly In chemistry and materials science, molecular self-assembly is the process by which molecules adopt a defined arrangement without guidance or management from an outside source. There are two types of self-assembly: intramolecular and intermo ...

molecular recognition The term molecular recognition refers to the specific interaction between two or more molecules through noncovalent bonding such as hydrogen bonding, metal coordination, hydrophobic forces, van der Waals forces, π-π interactions, halogen ...

, and

host–guest chemistry In supramolecular chemistry, host–guest chemistry describes inclusion compound, complexes that are composed of two or more molecules or ions that are held together in unique structural relationships by forces other than those of full covalent bond ...

Design

Foldamers can vary in size, but they are defined by the presence of noncovalent, nonadjacent interactions. This definition excludes molecules like poly(isocyanates) (commonly known as (

polyurethane Polyurethane (; often abbreviated PUR and PU) refers to a class of polymers composed of organic chemistry, organic units joined by carbamate (urethane) links. In contrast to other common polymers such as polyethylene and polystyrene, polyurethan ...

)) and poly(prolines) as they fold into helices reliably due to ''adjacent'' covalent interactions., Foldamers have a dynamic folding reaction nfolded → 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

The structure of a foldamer can often be predicted from its primary sequence. This process involves dynamic simulations of the folding equilibria at the atomic level under various conditions. This type of analysis may be applied to small proteins as well, however 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 In mathematics and its applications, the root mean square of a set of numbers x_i (abbreviated as RMS, or rms and denoted in formulas as either x_\mathrm or \mathrm_x) is defined as the square root of the mean square (the arithmetic mean of th ...

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 The viscosity of a fluid is a measure of its resistance to deformation at a given rate. For liquids, it corresponds to the informal concept of "thickness": for example, syrup has a higher viscosity than water. Viscosity quantifies the inte ...

pressure Pressure (symbol: ''p'' or ''P'') is the force applied perpendicular to the surface of an object per unit area over which that force is distributed. Gauge pressure (also spelled ''gage'' pressure)The preferred spelling varies by country a ...

, 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. Solvent often influences folding. For example, a folding pathway involving

hydrophobic collapse Hydrophobic collapse is a proposed process for the production of the 3-D conformation adopted by polypeptides and other molecules in polar solvents. The theory states that the nascent polypeptide forms initial secondary structure ( ɑ-helices and ...

would fold differently in a

nonpolar In chemistry, polarity is a separation of electric charge leading to a molecule or its chemical groups having an electric dipole moment, with a negatively charged end and a positively charged end. Polar molecules must contain one or more pola ...

solvent. This difference 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 In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing ...

(especially with

peptide bond In organic chemistry, a peptide bond is an amide type of covalent chemical bond linking two consecutive alpha-amino acids from C1 (carbon number one) of one alpha-amino acid and N2 ( nitrogen number two) of another, along a peptide or protein c ...

s) *

Pi stacking In chemistry, pi stacking (also called π–π stacking) refers to the presumptive attractive, noncovalent pi interactions (orbital overlap) between the pi bonds of aromatic rings. However this is a misleading description of the phenomena sin ...

* Solvophobic effects, which lead to

Van der Waals force In molecular physics, the van der Waals force is a distance-dependent interaction between atoms or molecules. Unlike ionic or covalent bonds, these attractions do not result from a chemical electronic bond; they are comparatively weak and t ...

s * Electrostatic attraction

Common designs

Foldamers are classified into three different categories: 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: Structure, Properties, and Applications" Stefan Hecht, Ivan Huc Eds. Wiley-VCH, Weinheim, 2007. The three designs described below deviate from Moore's strict definition of a foldamer, which excludes helical foldamers.

Peptidomimetic

Peptidomimetic foldamers often break the previously mentioned definition of foldamers as they often adopt

helical Helical may refer to: * Helix A helix () is a shape like a corkscrew or spiral staircase. It is a type of smooth space curve with tangent lines at a constant angle to a fixed axis. Helices are important in biology, as the DNA molecule is ...

structures. They represent a major landmark of foldamer research due to their design and capabilities. The largest groups of peptidomimetic consist of β –

peptides Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...

, 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 In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxyl ...

and

amino In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent su ...

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) they 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.

Nucleotidomimetic

Nucleotidomimetics do not generally qualify as foldamers. Most are designed to mimic single DNA bases,

nucleosides Nucleosides are glycosylamines that can be thought of as nucleotides without a phosphate group. A nucleoside consists simply of a nucleobase (also termed a nitrogenous base) and a five-carbon sugar (ribose or 2'-deoxyribose) whereas a nucleotid ...

, or

nucleotides Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules wi ...

in order to nonspecifically target DNA. These have several different medicinal uses including anti-cancer, anti-viral, and anti-fungal applications.

Abiotic

Abiotic foldamers are again organic molecules designed to exhibit dynamic folding. They exploit one or a few known key intermolecular interactions, as optimized by their design. One example is oligopyrroles that organize upon binding anions like chloride through hydrogen bonding (see figure). Folding is induced in the presence of an anion: the polypyrrole groups have little conformational restriction otherwise.

Other examples

* ''m''-Phenylene ethynylene oligomers are driven to fold into a helical conformation by

solvophobic force Solvophobic theory attempts to explain interactions between polar solvents and non-polar solutes. In the pure solvent, there are relatively strong cohesive forces between the solvent molecules due to hydrogen bonding or other polar interactions. Hen ...

s and aromatic stacking interactions. * β-peptides are composed of

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...

s containing an additional unit between the

amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent su ...

and

carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxyl ...

. They are more stable to enzymatic degradation and have been demonstrated to have antimicrobial activity. * Peptoids are ''N''-substituted polyglycines that utilize steric interactions to fold into polyproline type-I-like helical structures. * Aedamers that fold in aqueous solutions driven by hydrophobic and aromatic stacking interactions. * Aromatic Oligoamide Foldamers These examples are some of the largest and best structurally characterized Foldamers. * Arylamide foldamers,De novo design and in vivo activity of conformationally restrained antimicrobial arylamide foldamers. Choi. 2009
/ref> eg Brilacidin