chemistry Chemistry is the scientific study of the properties and behavior of matter. It is a physical science within the natural sciences that studies the chemical elements that make up matter and chemical compound, compounds made of atoms, molecules a ...

, a foldamer is a discrete chain molecule ( oligomer) that folds 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 residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

nucleic acid Nucleic acids are large biomolecules that are crucial in all cells and viruses. They are composed of nucleotides, which are the monomer components: a pentose, 5-carbon sugar, a phosphate group and a nitrogenous base. The two main classes of nuclei ...

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 wat ...

s to fold into well-defined conformations, such as α-helices and

β-sheet The beta sheet (β-sheet, also β-pleated sheet) is a common structural motif, motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone chain, backbon ...

s. The structure of a foldamer is stabilized by noncovalent interactions between nonadjacent

monomers A monomer ( ; ''wikt:mono-, mono-'', "one" + ''wikt:-mer, -mer'', "part") is a molecule that can chemical reaction, react together with other monomer molecules to form a larger polymer chain or two- or three-dimensional network in a process called ...

. 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,

molecular recognition Supramolecular chemistry refers to the branch of chemistry concerning Chemical species, chemical systems composed of a integer, discrete number of molecules. The strength of the forces responsible for spatial organization of the system range from w ...

, and host–guest chemistry.

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) is 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, polyurethane term ...

) and poly(prolines) as they fold into helices 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

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, as of 2024, 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, the root mean square (abbrev. RMS, or rms) of a set of values is the square root of the set's mean square. Given a set x_i, its RMS is denoted as either x_\mathrm or \mathrm_x. The RMS is also known as the quadratic mean (denote ...

deviation from the backbone atomic 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 Viscosity is a measure of a fluid's rate-dependent drag (physics), resistance to a change in shape or to movement of its neighboring portions relative to one another. For liquids, it corresponds to the informal concept of ''thickness''; for e ...

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 and eve ...

, 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. Solvents often influence folding. For example, a folding pathway involving hydrophobic collapse would fold differently in a nonpolar 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, collectively alter 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 (H-bond) is a specific type of molecular interaction that exhibits partial covalent character and cannot be described as a purely electrostatic force. It occurs when a hydrogen (H) atom, Covalent bond, covalently b ...

(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 cha ...

s) * Pi stacking * Solvophobic effects, which lead to hydrophobic collapse *

Van der Waals force In molecular physics and chemistry, the van der Waals force (sometimes 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 elec ...

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 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. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Dalton (unit), Da or more are called proteins. Chains of fewer t ...

, γ-peptides and δ-peptides, and the possible monomeric combinations. The

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the Proteinogenic amino acid, 22 α-amino acids incorporated into p ...

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), 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 nucleotide ...

, or

nucleotides Nucleotides are Organic compound, organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both o ...

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 a few known key intermolecular interactions, as optimized by their design. One example is oligopyrroles that organize upon binding anions like

chloride The term chloride refers to a compound or molecule that contains either a chlorine anion (), which is a negatively charged chlorine atom, or a non-charged chlorine atom covalently bonded to the rest of the molecule by a single bond (). The pr ...

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 forces 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 over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

s containing an additional unit between the

amine In chemistry, amines (, ) are organic compounds that contain carbon-nitrogen bonds. Amines are formed when one or more hydrogen atoms in ammonia are replaced by alkyl or aryl groups. The nitrogen atom in an amine possesses a lone pair of elec ...

and

carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an Substituent, R-group. The general formula of a carboxylic acid is often written as or , sometimes as with R referring to an organyl ...

. 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> such as brilacidin.