Noncovalent Interactions in Molecular Systems

Noncovalent interactions encompass a diverse array of attractive forces that govern the assembly, stability and function of molecular architectures without the formal sharing of electrons. From the directional hydrogen bond that underpins the double helix of DNA to subtle van der Waals contacts that drive protein folding, these interactions define the three-dimensional organisation of biological macromolecules, supramolecular assemblies and advanced materials. Recent years have seen growing recognition of less conventional forces such as n→π* interactions between adjacent carbonyl groups, halogen bonds mediated by anisotropic electron distribution, and aromatic-carbonyl contacts that confer specificity in molecular recognition. The interplay of electrostatics, dispersion and orbital delocalisation enables fine-tuning of conformational landscapes, reaction pathways and physicochemical properties. Harnessing this toolkit has unlocked new strategies for rational drug design, responsive materials, self-healing polymers and dynamic covalent frameworks. A mechanistic understanding of how weak forces cooperate and compete on the molecular level is central to innovations in catalysis, nanotechnology and biomolecular engineering, and it continues to reveal unexpected routes to functional complexity in both natural and synthetic systems.

Research from Nature Portfolio

Studies of gas-phase dipeptides have definitively characterised the role of n→π* interactions in stabilising common peptide conformations, confirming that lone pairs on one carbonyl can delocalise into the antibonding orbital of a neighbouring carbonyl and thereby influence secondary-structure preferences. Complementary work in small molecules and proteins has uncovered “reciprocal” carbonyl–carbonyl interactions, in which bidirectional electron delocalisation occurs between adjacent carbonyl pairs. These findings demonstrate that such subtle orbital effects are pervasive in unfolded proteins and polyesters, suggesting a broader contribution to folding energetics and local rigidity than previously appreciated.

Research from all publishers

Emerging investigations of aromatic-carbonyl interactions have revealed that the close approach of an arene face to a carbonyl carbon can produce stabilising contacts exploitable in supramolecular catalysis and sensing. In parallel, studies exploring Pauli-exclusion-driven n→π* interactions in collagen elucidate how such forces protect peptide bonds from hydrolysis in fossilised tissues, highlighting a role in long-term biomolecular preservation. Furthermore, protein-engineering research has demonstrated that selectively strengthening n→π* interactions at β-turns through amino-acid substitution can measurably enhance thermal stability, offering a design principle for robust protein therapeutics and industrial biocatalysts.

Noncovalent Interactions in Molecular Systems publication trend

The graph below shows the total number of articles in noncovalent interactions in molecular systems across all publications each year (not limited to Nature Index journals).

Technical terms

Hydrogen bond: Attractive interaction between an electronegative atom (e.g. O, N) and a hydrogen atom covalently bound to another electronegative atom.

n→π* interaction: Delocalisation of a lone-pair (n) electron from a donor atom into the antibonding π* orbital of an adjacent acceptor group, often carbonyl-based.

π–π stacking: Attractive overlap between the π-electron clouds of aromatic rings that stabilises relative orientations in molecular assemblies.

Halogen bond: Noncovalent attraction in which a halogen atom with an electrophilic region (σ-hole) interacts with a nucleophilic site on another molecule.

σ-hole: Localised region of positive electrostatic potential on a covalently bound halogen atom that facilitates halogen bonding.

References

1. Aromatic‐Carbonyl Interactions as an Emerging Type of Non‐Covalent Interactions. Advanced Science (2024).
2. Pauli Exclusion by n→π* Interactions: Implications for Paleobiology. ACS Central Science (2024).
3. Reciprocal carbonyl–carbonyl interactions in small molecules and proteins. Nature Communications (2017).
4. Unveiling the n→π* interactions in dipeptides. Communications Chemistry (2019).
5. Increasing protein stability by engineering the n → π* interaction at the β-turn. Chemical Science (2020).