Scientists discover mechanism driving molecular network formation

(Press-News.org) Covalent bonding is a widely understood phenomenon that joins the atoms of a molecule by a shared electron pair. But in nature, patterns of molecules can also be connected through weaker, more dynamic forces that give rise to supramolecular networks. These can self-assemble from an initial molecular cluster, or crystal, and grow into large, stable architectures.

Supramolecular networks are essential for maintaining the structure and function of biological systems. For example, to ‘eat’, cells rely on hexagonal supramolecular networks that self-assemble from units of the three-armed protein clathrin. Clathrin networks form bubbles around nutrients to bring them into the cell. Similarly, a protein called TRIM5a forms a hexagonal lattice that forms around HIV viruses, helping to disrupt their replication.

“This hexagonal network structure is omnipresent in nature – you can even see it at the macroscale in beehives, for example,” explains Maartje Bastings, head of the Programmable Biomaterials Lab (PBL) in EPFL’s School of Engineering.

For their latest study published in Nature Chemistry, the researchers from the PBL and the Laboratory for Bio- and Nano-Instrumentation (LBNI), led by Georg Fantner, used nanoengineered DNA strands in a three-point star shape to isolate and examine the different factors controlling crystalline supramolecular network formation. In the process, they discovered a “defining parameter” even more important than chemical bond strength or number.

‘Interface flexibility will always win’

Like human DNA, the composition of the three-point star DNA molecules varied by their sequences of nucleotides, which affected their interaction strength (affinity) with neighboring molecules. But for this study, the researchers introduced an additional variable: through nuanced changes in the lengths of the strands making up each of the monomers’ three arms, they were able to modulate the arms’ local and global flexibility.

Using high-speed atomic force microscopy, the team observed that the DNA stars with shorter, rigid ‘arms’ organized into stable hexagonal networks, while those with longer, more flexible arms were unable to form any large networks. Simulations revealed that the short arms were nearly four times more likely to be arranged in a parallel shape more conducive to connecting with other molecules, while the longer arms tended to splay too far apart to create stable connections. The researchers termed this variation interface flexibility.

“The interface where two molecules come together must be rigid; if one is flexible, there’s a lower chance the molecules will stay connected. Binding strength isn’t important – interface flexibility will always win. This goes against what’s been understood to date,” Bastings says.

Interestingly, the researchers also showed that interface flexibility can be fine-tuned: in flexible molecules, they were able to restore local rigidity at the binding interface enough to support network growth, while maintaining the molecules’ overall larger size. “This means that even globally flexible monomers can still grow into networks if the interface flexibility at the point of binding is controlled,” Bastings summarizes.

Build or destroy

Bastings says this work could change how scientists design proteins and other molecules for self-assembly, and create new opportunities for cellular nanotherapies. Targeted approaches could focus on rigidity in the design of new supramolecular networks from proteins, for example; or on inducing flexibility for the strategic breakdown or prevention of undesirable networks, like amyloid plaques seen in relation with Alzheimer’s disease. She also foresees applications in spintronics, where the self-assembly of well-defined nanoscale networks could help build next-generation electronics.

She credits the achievement to the initiative of the students in her lab and collaborators from the LBNI. And she doesn’t forget to give due recognition to the humble DNA molecule.

“Advances in interdisciplinary DNA nanotechnology, and in the control of properties at the atomic level, have made it possible to take DNA out of the genomic context and transform it into a workhorse for discovering global physical interactions – like interface flexibility."

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