Scientists unlock nature’s secret to super-selective binding

EPFL researchers have found that it is not just molecular density, but also pattern and structural stiffness, that control super-selective binding interactions between nanomaterials and protein surfaces. This breakthrough could help optimize existing approaches to virus prevention and cancer detection.

Much of biology boils down to the biophysical process of bonding: making a strong connection between one or more groups of atoms, called ligands, and their corresponding receptor molecule on a surface. A binding event is the first fundamental process that allows a virus to infect a host, or chemotherapy to fight cancer. But binding interactions – at least our understanding of them – have a “golden loop problem”: too few ligands on a molecule prevent it from binding stably to the right target, while too many can lead to unwanted side effects.

“When binding is triggered by a threshold of target receptor density, we call this binding ‘super-selective’, which is essential to prevent random interactions that could deregulate biological function“, explains Maartje Bastings, head of the Programmable Biomaterials Laboratory (PBL) at the School of Engineering. “Since nature does not usually complicate things, we wanted to know the minimum number of binding interactions that would still allow super-selective binding. to arrive. We also wanted to know if the model ligand the molecules are arranged in fact a difference in selectivity. It turns out that it is.”

Bastings and four from his Ph.D. students recently published a study in the Journal of the American Chemical Society which identifies the optimal number of ligands for super-selective binding: six. But they also found, to their delight, that the arrangement of these ligands– in a line, circle or triangle, for example – also had a significant impact on the effectiveness of the link. They dubbed the phenomenon “multivalent pattern recognition” or MPR.

“MPR opens up a whole new set of hypotheses about how molecular communication in biological and immunological processes might work. For example, the SARS-CoV-2 virus has a spike protein template that it uses to bind to cell surfaces, and those templates could be really critical when it comes to selectivity.”

From coronaviruses to cancer

Because it is double helix structure is so precise and so well understood that DNA is the perfect model molecule for PBL research. For this study, the team designed a rigid disk made entirely of DNA, where the position and number of all ligand molecules could be precisely controlled. After designing a series of ligand-receptor architectures to explore how density, geometry and nano-spacing influenced binding super-selectivity, the team realized that stiffness was a key factor. “The more flexible it is, the less precise it is,” says Bastings.

“Our goal was to carve out a place design principles in as minimal a way as possible, so that every ligand molecule participates in the binding interaction. What we have now is a very nice toolbox to further exploit super-selective binding interactions in biological systems.”

The applications for such a “toolbox” are far-reaching, but Bastings sees three immediately valid uses. “Like it or not,” she says, “the SARS-CoV-2 virus is currently a first thought in virological applications. With the information from our study, one could imagine developing a super-selective particle with ligand motifs designed to bind to the virus to prevent infection, or to block a cell site so that the virus cannot infect it.”

Diagnostics and therapeutics such as chemotherapy could also benefit from super-selectivity, which could enable more reliable binding with cancer cells, for which certain receptor molecules are known to have higher density. In this case, healthy cells would remain undetected, greatly reducing side effects.

Finally, such selectivity engineering could offer key insights into complex interactions within the immune system. “Because we can now precisely play with patterns of what’s happening at binding sites, we can, in a sense, potentially ‘communicate’ with the immune system,” says Bastings.