From Coils to Cages: Self-assembly strategies that mimic protein assembly, such as the formation of viral coats, often begin with simpler peptide assemblies. Fletcher et al. (p. 595 , published online 11 April; see the Perspective by Ardejani and Orner ) designed two coiled-coil peptide motifs, a heterodimer, and a homotrimer. Both peptides contained cysteine residues and could link through disulfide bonds, so that the trimer could form the vertices of a hexagonal network and the dimer its edges. However, these components are flexible and, rather than form extended sheets, they closed to form particles ∼100 nanometers in diameter.

Hydrogels are hydrated polymer networks with applications in biotechnology and medicine. When created from alpha-helical peptides with engineered peptide sequences, their formation mechanisms can be controlled, leading to diverse properties. For instance, those with hydrogen-bonded networks melt on heating, but those formed through hydrophobic interactions strengthen when warmed. Biocompatible hydrogels have a wide variety of potential applications in biotechnology and medicine, such as the controlled delivery and release of cells, cosmetics and drugs, and as supports for cell growth and tissue engineering1. Rational peptide design and engineering are emerging as promising new routes to such functional biomaterials2,3,4. Here, we present the first examples of rationally designed and fully characterized self-assembling hydrogels based on standard linear peptides with purely α-helical structures, which we call hydrogelating self-assembling fibres (hSAFs). These form spanning networks of α-helical fibrils that interact to give self-supporting physical hydrogels of >99% water content. The peptide sequences can be engineered to alter the underlying mechanism of gelation and, consequently, the hydrogel properties. Interestingly, for example, those with hydrogen-bonded networks of fibrils melt on heating, whereas those formed through hydrophobic fibril–fibril interactions strengthen when warmed. The hSAFs are dual-peptide systems that gel only on mixing, which gives tight control over assembly5. These properties raise possibilities for using the hSAFs as substrates in cell culture. We have tested this in comparison with the widely used Matrigel substrate, and demonstrate that, like Matrigel, hSAFs support both growth and differentiation of rat adrenal pheochromocytoma cells for sustained periods in culture.

Protein–carbohydrate interactions play pivotal roles in health and disease. However, defining and manipulating these interactions has been hindered by an incomplete understanding of the underlying fundamental forces. To elucidate common and discriminating features in carbohydrate recognition, we have analyzed quantitatively X-ray crystal structures of proteins with noncovalently bound carbohydrates. Within the carbohydrate-binding pockets, aliphatic hydrophobic residues are disfavored, whereas aromatic side chains are enriched. The greatest preference is for tryptophan with an increased prevalence of 9-fold. Variations in the spatial orientation of amino acids around different monosaccharides indicate specific carbohydrate C–H bonds interact preferentially with aromatic residues. These preferences are consistent with the electronic properties of both the carbohydrate C–H bonds and the aromatic residues. Those carbohydrates that present patches of electropositive saccharide C–H bonds engage more often in C...

Proteins rely on a combination of intramolecular forces to form and stabilize their structures. A careful comparison of computational analysis and high-resolution crystal structures now indicates that the n→π* interaction merits inclusion in this group. Hydrogen bonds between backbone amides are common in folded proteins. Here, we show that an intimate interaction between backbone amides also arises from the delocalization of a lone pair of electrons (n) from an oxygen atom to the antibonding orbital (π*) of the subsequent carbonyl group. Natural bond orbital analysis predicted significant n→π* interactions in certain regions of the Ramachandran plot. These predictions were validated by a statistical analysis of a large, non-redundant subset of protein structures determined to high resolution. The correlation between these two independent studies is striking. Moreover, the n→π* interactions are abundant and especially prevalent in common secondary structures such as α-, 310- and polyproline II helices and twisted β-sheets. In addition to their evident effects on protein structure and stability, n→π* interactions could have important roles in protein folding and function, and merit inclusion in computational force fields.

Building with alphahelical coiled coils: Understanding how proteins fold into well-defined three-dimensional structures has been a longstanding challenge. Increased understanding has led to increased success at designing proteins that mimic existing protein folds. This raises the possibility of custom design of proteins with structures not seen in nature. Thomson et al. describe the design of channelcontaining α-helical barrels, and Huang et al. designed hyperstable helical bundles. Both groups used rational and computational design to make new protein structures based on α-helical coiled coils but took different routes to reach different target structures. Science , this issue p. 485 , p. 481