Original microscopy knowledge on totally different ligand patterns on DNA supplies Credit: © Bastings/PBL EPFL
EPFL researchers have discovered that controlling super-selective binding interactions between nanomaterials and protein surfaces requires not solely adjusting the molecular density but in addition the sample and structural rigidity.
Researchers at Ecole Polytechnique Fédérale de Lausanne (EPFL) have found that controlling super-selective binding interactions between nanomaterials and protein surfaces not solely will depend on molecular density but in addition on sample and structural rigidity. This breakthrough has the potential to optimize present strategies for virus prevention and most cancers detection.
So a lot of biology comes all the way down to the biophysical strategy of binding: making a robust connection between a number of teams of atoms – referred to as ligands – to their corresponding receptor molecule on a floor. A binding occasion is the primary basic course of that enables a virus to contaminate a number, or chemotherapy to struggle most cancers. But binding interactions – at the least, our understanding of them – have a ‘Goldilocks problem’: too few ligands on one molecule make it unimaginable to stably bind with the right goal, whereas too many may end up in undesirable unintended effects.
“When binding is triggered by a threshold density of target receptors, we call this “super-selective” binding, which is essential to stopping random interactions that would dysregulate organic operate,” explains Maartje Bastings, head of the Programmable Biomaterials Laboratory (PBL) within the School of Engineering. “Since nature typically doesn’t overcomplicate things, we wanted to know the minimum number of binding interactions that would still allow for super-selective binding to occur. We were also interested to know whether the pattern the ligand molecules are arranged in makes a difference in selectivity. As it turns out, it does!”
Bastings and 4 of her Ph.D. college students have not too long ago printed a examine within the Journal of the American Chemical Society that identifies the optimum ligand quantity for super-selective binding: six. But additionally they discovered, to their pleasure, that the association of those ligands – in a line, circle, or triangle, for instance – additionally considerably impacted binding efficacy. They have dubbed the phenomenon “multivalent pattern recognition” or MPR.
“MPR opens up a complete new set of hypotheses round how molecular communication in organic and immunological processes may work. For instance, the SARS-CoV-2 virus has a pattern of spike proteins that it uses to bind to cell surfaces, and these patterns could be really critical when it comes to selectivity.”
From coronaviruses to cancer
Because its double helix structure is so precise and well understood, DNA is the perfect model molecule for the PBL’s research. For this study, the team designed a rigid disk made entirely out of DNA, where the position and number of all ligand molecules could be precisely controlled. After engineering a series of ligand-receptor architectures to explore how density, geometry, and nano-spacing influenced binding super-selectivity, the team realized that rigidity was a key factor. “The more flexible, the less precise,” Bastings summarizes.
“Our aim was to carve out design principles in as minimalist a way as possible so that every ligand molecule participates in the binding interaction. What we now have is a really 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 valuable uses. “Like it or not,” she says, “the SARS-CoV-2 virus is currently a first thought when it comes to virological applications. With the insights from our study, one could imagine developing a super-selective particle with ligand patterns designed to bind with 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 allow for more reliable binding with cancer cells, for which certain receptor molecules are known to have a higher density. In this case, healthy cells would remain undetected, drastically reducing side effects.
Finally, such selectivity engineering could offer key insights into complex interactions within the immune system. “Because we can now play precisely with patterns of what happens at binding sites, we can, in a sense, potentially ‘communicate’ with the immune system,” Bastings says.
Reference: “Multivalent Pattern Recognition through Control of Nano-Spacing in Low-Valency Super-Selective Materials” by Hale Bila, Kaltrina Paloja, Vincenzo Caroprese, Artem Kononenko and Maartje M.C. Bastings, 16 November 2022, Journal of the American Chemical Society.
DOI: 10.1021/jacs.2c08529
