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The immune system exploits a wide range of strategies to combine sensitivity with selectivity for optimal response. We propose a generic physical mechanism that allows tuning the location and steepness of the response threshold of cellular processes activated by multivalent binding. The mechanism is based on the possibility to modulate the attraction between membrane receptors. We use theory and simulations to show how tuning interreceptor attraction can enhance or suppress the binding of multivalent ligand-coated particles to surfaces. The changes in the interreceptor attraction less than the thermal energykBTcan selectively switch the receptor-clustering and activation on or off in an almost step-wise fashion, which we explain by near-critical receptor density fluctuations. We also show that the same mechanism can efficiently regulate the onset of endocytosis for,e.g., drug delivery vehicles.
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Avidity and surface mobility in multivalent ligand–receptor binding
Targeted drug delivery relies on two physical processes: the selective binding of a therapeutic particle to receptors on a specific cell membrane, followed by transport of the particle across the membrane. In this article, we address some of the challenges in controlling the thermodynamics and dynamics of these two processes by combining a simple experimental system with a statistical mechanical model. Specifically, we characterize and model multivalent ligand–receptor binding between colloidal particles and fluid lipid bilayers, as well as the surface mobility of membrane-bound particles. We show that the mobility of the receptors within the fluid membrane is key to both the thermodynamics and dynamics of binding. First, we find that the particle-membrane binding free energy—or avidity—is a strongly nonlinear function of the ligand–receptor affinity. We attribute the nonlinearity to a combination of multivalency and recruitment of fluid receptors to the binding site. Our results also suggest that partial wrapping of the bound particles by the membrane enhances avidity further. Second, we demonstrate that the lateral mobility of membrane-bound particles is also strongly influenced by the recruitment of receptors. Specifically, we find that the lateral diffusion coefficient of a membrane-bound particle is dominated by the hydrodynamic drag against the aggregate of receptors within the membrane. These results provide one of the first direct validations of the working theoretical framework for multivalent interactions. They also highlight that the fluidity and elasticity of the membrane are as important as the ligand–receptor affinity in determining the binding and transport of small particles attached to membranes.
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- Award ID(s):
- 1710112
- PAR ID:
- 10293404
- Date Published:
- Journal Name:
- Nanoscale
- Volume:
- 13
- Issue:
- 29
- ISSN:
- 2040-3364
- Page Range / eLocation ID:
- 12602 to 12612
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/D1NR02083H
