Nano and biology
Peptides at the nanoscale: self-assembly, stability and the body
Peptides sit at an interesting crossroads in nanoscience. They are small biological molecules, but they can also be designed as building blocks that fold and stack into fibres, tubes, sheets and gels only a few nanometres across. This page follows the story from the chemistry of assembly to how researchers describe peptides in biological surroundings.
What a peptide is
The Wikipedia article on peptides defines them as short chains of amino acids linked by peptide bonds. Longer unbroken chains are called polypeptides, and those with a molecular mass of 10,000 daltons or more are called proteins; chains of fewer than twenty amino acids are called oligopeptides, a class that includes dipeptides, tripeptides and tetrapeptides. A peptide is usually a linear chain with a free amine group at one end and a carboxyl group at the other; ring-shaped peptides form a separate class.
For a materials scientist, that description suggests a useful property. Amino acids differ in charge, size and affinity for water, so choosing a sequence means choosing where to place charges, oily patches and hydrogen-bonding groups along a chain, and those choices decide how chains pack against one another. The same logic governs how a protein folds; in the laboratory it can make short chains assemble into structures of the designer's choosing.
From a membrane to fibres and tubes
An early example came in 1993. In the Proceedings of the National Academy of Sciences, Zhang and colleagues reported a sixteen-residue peptide with a regular pattern of charged and uncharged amino acids that, on the addition of salt, spontaneously assembled into a macroscopic membrane. Their abstract describes a network of interwoven filaments seen by scanning electron microscopy, approximately 10 to 20 nm in diameter, and a membrane that resisted heat, acid, alkali and several protein-digesting enzymes.
In 2001, in Science, Hartgerink and colleagues took a different design, the peptide-amphiphile: a peptide sequence joined to an oily tail, so that the molecule has a water-loving end and a water-avoiding end. Their abstract reports that a change of pH made the molecules assemble into a nanostructured fibrous scaffold that the authors compared to the extracellular matrix, the network of protein fibres around cells in tissues. Once cross-linked, the fibres directed the growth of hydroxyapatite crystals aligned along their axes, the same alignment seen between collagen fibrils and mineral in bone.
Two years later, Reches and Gazit showed in Science how short a building block could be. Their abstract reports that a two-residue motif built from phenylalanine assembled into discrete, stiff nanotubes, which they used as moulds to cast silver nanowires before removing the peptide with an enzyme. The same dipeptide made from the mirror-image form of the amino acid gave tubes that resisted enzymatic breakdown, a detail that returns below.
Why peptides assemble
A 2016 review in Chemical Society Reviews by Wang and colleagues sets out the physical chemistry. Its abstract describes peptides as among the most popular programmable building blocks for self-assembly and explains that ordered peptide nanostructures form through several non-covalent interactions acting together: hydrogen bonding, stacking of aromatic rings, electrostatic attraction, hydrophobic effects and van der Waals forces. The review stresses that the process is driven mainly by thermodynamics, but that kinetics, the pathway and speed of assembly, is also critical in deciding which structure forms.
That balance is familiar from the rest of self-assembly. A peptide that could form either a fibre or a sheet may form one or the other depending on concentration, pH, temperature and how fast conditions change, which is why papers in the field describe preparation in such detail: a change that looks trivial can produce a different material.
Scaffolds and gels
Many assembling peptides form networks that trap large amounts of water, producing soft gels. Such hydrogels are studied partly because they resemble, at the nanoscale, the fibrous matrix around cells in tissues, a comparison the 2001 peptide-amphiphile paper drew explicitly. Research reviews describe work on building cell-attachment sequences and other functional segments into self-assembling peptides, so that the resulting nanostructures carry chemical signals along their fibres. That is a laboratory research area, pursued mostly in cell cultures and model systems.
Peptides and nanostructures in biological surroundings
In a biological fluid, several processes act on a peptide or nanostructure, and researchers study each of them.
Enzymatic breakdown. The Wikipedia article on proteolysis describes the breakdown of proteins into smaller polypeptides or amino acids, a process typically catalysed by enzymes called proteases. It notes that without such catalysis the hydrolysis of peptide bonds is extremely slow, taking hundreds of years; with enzymes present it can be rapid. Peptides share the same bonds and meet the same enzymes.
Persistence over time. Pharmacologists describe how long a substance remains in circulation using the idea of a half-life, the time taken for its concentration in blood plasma to fall to half its maximum. The idea applies to any substance.
Coating by proteins. A nanoparticle in blood quickly acquires a coating of adsorbed proteins, called a corona. A 2017 review in Seminars in Immunology by Barbero and colleagues describes the corona as giving a nanoparticle the biological identity that the immune system will detect, and explains that its formation depends on the particle's composition, size, shape and surface as well as on the surrounding medium. Size also influences how particles are distributed and cleared by the body's filtering organs; the nanomedicine page discusses reviews of the corona and of particle size in more detail.
Why chemists study stabilisation
These processes explain a large body of chemical research on peptides. A 2022 review in Pharmaceuticals by Al Musaimi and colleagues identifies two shortcomings of peptides when they are used as delivery vectors or imaging molecules: poor metabolic stability and a short half-life. It surveys structural modifications and delivery strategies that researchers have developed to increase resistance to enzymatic degradation, with particular attention to cell-penetrating peptides and to stapled peptides, which it reports have shown greater stability than their parent peptides. The enzyme-resistant mirror-image nanotubes of Reches and Gazit echo the same idea.
Other reviews examine packaging peptides within self-assembled carriers, describing design strategies in which peptide nanostructures are built before use or form in place. Like the rest of this literature, that work is research in progress, and it is best read as a record of what has been tried and measured rather than as a set of settled results.
Peptides thus bring together the field's main ideas: molecular design, self-assembly, surface chemistry and the behaviour of small objects in complex surroundings. The page on 2001–2002 shows how prominent the subject already was in the journals of that period.