Jirí Cerný and Pavel Hobza at the Academy of Sciences of the Czech Republic, Prague, study the role non-covalent interactions play in the structure, stability and functions of biomolecules.

Chemistry is based on formation and decay of the covalent bond. The bond is one of the most successful concepts in science and it is possible to state that present theoretical and quantum chemistry can fully describe its nature. Biology needs much weaker interactions and covalent bonding clearly does not fulfil this requirement. So, besides strong covalent bonding, nature has been forced to create other, considerably weaker bonds to represent the basic machinery for the very existence of life. These bonds are called non-covalent interactions and their nature is completely different from that of the covalent bond. Non-covalent interactions act between different molecules as well as between parts of a single molecule.

Non-covalent interactions are evident at the macroscopic as well as the microscopic level: they are responsible for a gecko's ability to climb smooth vertical surfaces - even flat glass. Contacts between keratinous hairs, or setae, on its feet and the surface are responsible for surprisingly strong adhesion.

Crossing the scales: non-covalent interactions feature throughout nature, from the folding of DNA to a gecko's ability to climb walls

Other examples of non-covalent interactions are less spectacular but more important for nature. Firstly, water - a prerequisite for life. Non-covalent interactions are responsible for the very existence of the liquid phase (and solvation phenomena), but water in particular. Water possesses some very specific properties, such as melting and boiling temperatures, that differ greatly from those of other isoelectronic systems (methane, ammonia). These differences are explained by the existence of specific non-covalent interactions not present in the other systems.

Secondly, non-covalent interactions are responsible for the structure of biomacromolecules such as DNA, RNA and proteins. It is well-known that a biomacromolecule's function is determined mainly by its structure.

Thirdly, non-covalent interactions play a key role in molecular recognition, one of the most important processes in life. This process ensures extremely high fidelity in information transfer, for instance in transcribing and using the genetic information stored in DNA and RNA.

The unique role of non-covalent interactions in biology is based not only on easy formation of molecular complexes but also on their easy decomposition. For example, DNA should be stiff enough to safely store genetic information, yet simultaneously soft enough to allow it to unwind when the information is to be reproduced. Evolution has evidently selected non-covalent interactions over the too strong (approximately 10-100 times) covalent ones.

While theoretical description of covalent interactions is routine nowadays, description of non-covalent interactions remains one of the most difficult tasks in computational science. Due to their softness, non-covalent interactions are difficult to study theoretically and experimentally, and typically a complete picture is obtained only by combining the two techniques.

Two main interaction motifs (planar hydrogen-bonded and vertical stacked) exist between the building blocks of the most important biomacromolecules: DNA and proteins. The bonding in planar hydrogen-bonded DNA base pairs and amino acid pairs is well understood, but the role of the vertical stacking interactions, their origin and magnitude, was unclear until recently. Only the most accurate calculations of both interaction motifs revealed their relative importance and biological roles. It is now clear, and it is surprising, that it is the stacking that contributes dominantly to DNA stability. Much stronger hydrogen bonding actually destabilises the double helical structure.

The future of molecular biology will be defined by our understanding of non-covalent interactions. Only through these can we truly interpret biological processes at the molecular level.

Read Cerný and Hobza's perspective 'Non-covalent interactions in biomacromolecules' in a forthcoming issue of Physical Chemistry Chemical Physics.