In chemistry, 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 residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

s, nucleic acids, and polysaccharides 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 ear ...

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 Mo ...

. 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 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.

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 units joined by carbamate (urethane) links. In contrast to other common polymers such as polyethylene and polystyrene, polyurethane is produced from ...

)) 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 Biomolecular structure is the intricate folded, three-dimensional shape that is formed by a molecule of protein, DNA, or RNA, and that is important to its function. The structure of these molecules may be considered at any of several length s ...

. 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 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 and e ...

, 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 polar ...

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 An intermolecular force (IMF) (or secondary force) is the force that mediates interaction between molecules, including the electromagnetic forces of attraction or repulsion which act between atoms and other types of neighbouring particles, e.g. a ...

noncovalent interactions.

Noncovalent interactions

Noncovalent

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 a l ...

(especially with peptide bonds) * Pi stacking * 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 th ...

s * Electrostatic attraction

Common designs

Foldamers are classified into three different categories:

peptidomimetic A peptidomimetic is a small protein-like chain designed to mimic a peptide. They typically arise either from modification of an existing peptide, or by designing similar systems that mimic peptides, such as peptoids and β-peptides. Irrespective ...

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, the mathematical concept for the shape * Helical engine, a proposed spacecraft propulsion drive * Helical spring, a coilspring * Helical plc, a British property company, once a maker of steel bar stock * Helicoil A t ...

structures. They represent 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 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. Carboxylic ...

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 ...

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 nucleot ...

, 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 with ...

in order to nonspecifically target DNA. These have several different medicinal uses including

anti-cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal ble ...

anti-viral Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Unlike most antibiotics, antiviral drugs do ...

, 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 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 hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...

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 Hydrogen is the chemical element wi ...

and carboxylic acid. They are more stable to

enzymatic Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. ...

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