C. Linne
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Weak multivalent interactions govern a large variety of biological processes like cell–cell adhesion and virus–host interactions. These systems distinguish sharply between surfaces based on receptor density, known as superselectivity. Present experimental studies typically involve tens or hundreds of interactions, resulting in a high entropic contribution leading to high selectivities. However, if, and if so how, systems with few ligands, such as multi-domain proteins and bacteriophages binding to their host, show superselective behavior is an open question. Here, we address this question with a multivalent experimental model system based on star shaped branched DNA nanostructures (DNA nanostars) with each branch featuring a single stranded overhang that binds to complementary receptors on a target surface. Each DNA nanostar possesses a fluorophore, to directly visualize DNA nanostar surface adsorption by total internal reflection fluorescence microscopy (TIRFM). We observe that DNA nanostars can bind superselectively to surfaces and bind optimally at a valency of three, for a given binding strength and concentration. We explain this optimum by extending the current theory with interactions between DNA nanostar binding sites (ligands). Our results add to the understanding of multivalent interactions, by identifying cooperative mechanisms that lead to optimal selectivity, and providing quantitative values for the relevant parameters. These findings inspire additional design rules which improve future work on selective targeting in directed drug delivery.
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Weak multivalent interactions govern a large variety of biological processes like cell–cell adhesion and virus–host interactions. These systems distinguish sharply between surfaces based on receptor density, known as superselectivity. Present experimental studies typically involve tens or hundreds of interactions, resulting in a high entropic contribution leading to high selectivities. However, if, and if so how, systems with few ligands, such as multi-domain proteins and bacteriophages binding to their host, show superselective behavior is an open question. Here, we address this question with a multivalent experimental model system based on star shaped branched DNA nanostructures (DNA nanostars) with each branch featuring a single stranded overhang that binds to complementary receptors on a target surface. Each DNA nanostar possesses a fluorophore, to directly visualize DNA nanostar surface adsorption by total internal reflection fluorescence microscopy (TIRFM). We observe that DNA nanostars can bind superselectively to surfaces and bind optimally at a valency of three, for a given binding strength and concentration. We explain this optimum by extending the current theory with interactions between DNA nanostar binding sites (ligands). Our results add to the understanding of multivalent interactions, by identifying cooperative mechanisms that lead to optimal selectivity, and providing quantitative values for the relevant parameters. These findings inspire additional design rules which improve future work on selective targeting in directed drug delivery.
To bind or not to bind
DNA mediated multivalent interactions lead to superselectivity
To bind two entities together, an attractive interaction is needed. In biological systems, such interactions are often between ligands and receptors. But this interaction constantly breaks and forms because it is (too) weak. To ensure a lasting bond, the system can form multiple weak bonds that form an overall strong bond – similar to velcro. An interesting feature of aweak multivalent systemis the sharp discrimination between surfaces based on receptor density. That means that when multivalent particles encounter surfaces with the specific receptor but different densities, they will most likely bind to the surface with the highest density, because it has the highest binding probability. This phenomenon is called superselectivity and emerges from the large entropic contribution in amultivalent system: The more ligands and receptors are involved in the binding, the more possibilities the system has to form a bond and hence a large entropy. In this thesis we investigate how the interaction strength and entropy influences superselective binding. In doing so, we study superselective binding of microparticleswith hundreds of interactions and, additionally, particles with only few interactions of the size of nanometers.
...
To bind two entities together, an attractive interaction is needed. In biological systems, such interactions are often between ligands and receptors. But this interaction constantly breaks and forms because it is (too) weak. To ensure a lasting bond, the system can form multiple weak bonds that form an overall strong bond – similar to velcro. An interesting feature of aweak multivalent systemis the sharp discrimination between surfaces based on receptor density. That means that when multivalent particles encounter surfaces with the specific receptor but different densities, they will most likely bind to the surface with the highest density, because it has the highest binding probability. This phenomenon is called superselectivity and emerges from the large entropic contribution in amultivalent system: The more ligands and receptors are involved in the binding, the more possibilities the system has to form a bond and hence a large entropy. In this thesis we investigate how the interaction strength and entropy influences superselective binding. In doing so, we study superselective binding of microparticleswith hundreds of interactions and, additionally, particles with only few interactions of the size of nanometers.
Journal article
(2021)
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Christine Linne, Daniele Visco, Stefano Angioletti-Uberti, Liedewij Laan, Daniela J. Kraft
Reliably distinguishing between cells based on minute differences in receptor density is crucial for cell-cell or virus-cell recognition, the initiation of signal transduction, and selective targeting in directed drug delivery. Such sharp differentiation between different surfaces based on their receptor density can only be achieved by multivalent interactions. Several theoretical and experimental works have contributed to our understanding of this "superselectivity." However, a versatile, controlled experimental model system that allows quantitative measurements on the ligand-receptor level is still missing. Here, we present a multivalent model system based on colloidal particles equipped with surface-mobile DNA linkers that can superselectively target a surface functionalized with the complementary mobile DNA-linkers. Using a combined approach of light microscopy and Foerster resonance energy transfer (FRET), we can directly observe the binding and recruitment of the ligand-receptor pairs in the contact area. We find a nonlinear transition in colloid-surface binding probability with increasing ligand or receptor concentration. In addition, we observe an increased sensitivity with weaker ligand-receptor interactions, and we confirm that the timescale of binding reversibility of individual linkers has a strong influence on superselectivity. These unprecedented insights on the ligand-receptor level provide dynamic information into the multivalent interaction between two fluidic membranes mediated by both mobile receptors and ligands and will enable future work on the role of spatial-temporal ligand-receptor dynamics on colloid-surface binding.
...
Reliably distinguishing between cells based on minute differences in receptor density is crucial for cell-cell or virus-cell recognition, the initiation of signal transduction, and selective targeting in directed drug delivery. Such sharp differentiation between different surfaces based on their receptor density can only be achieved by multivalent interactions. Several theoretical and experimental works have contributed to our understanding of this "superselectivity." However, a versatile, controlled experimental model system that allows quantitative measurements on the ligand-receptor level is still missing. Here, we present a multivalent model system based on colloidal particles equipped with surface-mobile DNA linkers that can superselectively target a surface functionalized with the complementary mobile DNA-linkers. Using a combined approach of light microscopy and Foerster resonance energy transfer (FRET), we can directly observe the binding and recruitment of the ligand-receptor pairs in the contact area. We find a nonlinear transition in colloid-surface binding probability with increasing ligand or receptor concentration. In addition, we observe an increased sensitivity with weaker ligand-receptor interactions, and we confirm that the timescale of binding reversibility of individual linkers has a strong influence on superselectivity. These unprecedented insights on the ligand-receptor level provide dynamic information into the multivalent interaction between two fluidic membranes mediated by both mobile receptors and ligands and will enable future work on the role of spatial-temporal ligand-receptor dynamics on colloid-surface binding.