Avidity and surface mobility in multivalent ligand-receptor binding

TL;DR

This study combines experiments and a statistical mechanical model to analyze how receptor mobility and multivalency influence ligand-receptor binding strength and particle mobility on cell membranes.

Contribution

It introduces a model linking membrane fluidity and receptor recruitment to binding avidity and particle diffusion, validated by experimental data.

Findings

Binding free energy is a nonlinear function of ligand-receptor affinity.

Receptor recruitment enhances avidity and particle binding.

Membrane fluidity significantly affects particle mobility and binding dynamics.

Abstract

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.