Computational investigation of multivalent binding of a ligand coated particle: Role of shape, size and ligand heterogeneity from a free energy landscape perspective

TL;DR

This study uses multiscale modeling to analyze how shape, size, and ligand heterogeneity influence the binding efficacy of ligand-coated particles, providing insights for designing targeted delivery systems and understanding cell adhesion.

Contribution

The paper introduces a multiscale modeling framework combining molecular dynamics and continuum models to study multivalent binding, accounting for molecular details and configurational entropy effects.

Findings

Particles smaller than 350 nm have binding avidity influenced by enthalpy-entropy competition.

Anisotropic particles exhibit higher multivalent binding than spherical ones.

Ligand composition variations can change binding avidity without affecting multivalency.

Abstract

We utilize a multiscale modeling framework to study the effect of shape, size and ligand composition on the efficacy of binding of a ligand-coated-particle to a substrate functionalized with the target receptors. First, we show how molecular dynamics (MD) along with Steered MD calculations can be used to accurately parameterize the molecular binding free energy and the effective spring constant for a receptor-ligand pair. We demonstrate this for two ligands that bind to the $\alpha_5\beta_1$-domain of integrin. Next, we show how these effective potentials can be used to build computational models at the meso- and continuum- scales. These models incorporate the molecular nature of the receptor-ligand interactions and yet provide an inexpensive route to study the multivalent interaction of receptors and ligands through the construction of Bell potentials customized to the molecular identities. We quantify the binding efficacy of the ligand-coated-particle in terms of its multivalency, binding free energy landscape and the losses in the configurational entropies. We show that (i) the binding avidity for particle sizes less than $350$ nm is set by the competition between the enthalpic and entropic contributions while that for sizes above $350$ nm is dominated by the enthalpy of binding, (ii) anisotropic particles display higher multivalent binding compared to spherical particles and (iii) variations in ligand composition can alter binding avidity without altering the average multivalency. The methods and results presented here have wide applications in the rational design of functionalized carriers and also in understanding cell adhesion.