Researchers at Ecole Polytechnique Fédérale de Lausanne (EPFL) in Switzerland have developed a DNA toolbox that allows researchers to explore binding interactions between ligands and their respective receptors based on receptor density and arrangement. The basis for many pharmacological interactions between drugs and cells, and indeed many physiological or pathological interactions involving biological signaling molecules, involves a molecule, termed a ligand, binding to a receptor that is typically present on the cell membrane. This binding is highly specific, but it can be influenced by the density of ligands present. However, this latest research also casts light on some other underappreciated factors that can significantly affect ligand/receptor binding, including ligand arrangement and structural rigidity. To test these interactions and pave the way for more effective therapies, the researchers created a DNA-based toolbox that lets them test the factors affecting binding more easily.
Ligand/receptor binding is a fundamental biological process that can be exploited by humans and pathogens to achieve their respective ends. In the case of humans, we typically develop drugs to target certain receptors to achieve a therapeutic effect. In the case of certain viruses, they can bind to receptors as a way to gain access to the inside of our cells. SARS-CoV-2 binds the ACE-2 receptor to gain access to our nasal and lung cells, for example. Understanding these processes in more detail allows us to affect them in beneficial ways, such as preventing the virus from entering cells.
Schematic depicting different types of binding interactions © Bastings/PBL EPFL
“When binding is triggered by a threshold density of target receptors, we call this “super-selective” binding, which is key to preventing random interactions that could dysregulate biological function,” said Maartje Bastings, a researcher involved in the study. “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!”
Original microscopy data on different ligand patterns on DNA materials © Bastings/PBL EPFL
To study binding interactions, the researchers created a disc from DNA. DNA is well understood, and the researchers therefore chose it as a way to study binding. They also knew how to engineer the disc so that they could control the precise number and pattern of ligands on it. The researchers had already identified that six ligands is the ideal number to assure super-selective binding, but using their new toolkit they also discovered that the arrangement of the ligands, whether it be in a line, a triangle, or a circle, also has a large effect on binding. They have called this process “multivalent pattern recognition”.
Geometric hexavalent ligand patterns vs random (far right) © Bastings/PBL EPFL
“Like it or not, the SARS-CoV-2 virus is currently a first thought when it comes to virological applications,” said Bastings. “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.”
Top image: Visualization of protein complexity on a cell surface © PBL EPFL/Christine Lavanchy
Study in Journal of the American Chemical Society: Multivalent Pattern Recognition through Control of Nano-Spacing in Low-Valency Super-Selective Materials