Binding kinetics of membrane-anchored receptors and ligands: molecular dynamics simulations and theory

TL;DR

This study combines molecular dynamics simulations and theoretical modeling to analyze how membrane properties and protein anchoring influence the binding kinetics of membrane-anchored receptors and ligands, revealing key factors affecting adhesion.

Contribution

It introduces a detailed theory linking membrane separation, roughness, and protein anchoring to binding kinetics, supported by simulation data for lipid-anchored and transmembrane proteins.

Findings

Lipid-anchored proteins have lower binding constants and on-rate constants than transmembrane proteins.

Tilt of receptor-ligand complexes influences binding at various membrane separations.

Theoretical model accurately describes the dependence of binding kinetics on membrane and protein parameters.

Abstract

The adhesion of biological membranes is mediated by the binding of membrane-anchored receptor and ligand proteins. Central questions are how the binding kinetics of these proteins is affected by the membranes and by the membrane anchoring of the proteins. In this article, we (i) present detailed data for the binding of membrane-anchored proteins from coarse-grained molecular dynamics simulations, and (ii) provide a theory that describes how the binding kinetics depends on the average separation and thermal roughness of the adhering membranes, and on the anchoring, lengths, and length variations of the proteins. An important element of our theory is the tilt of bound receptor-ligand complexes and transition-state complexes relative to the membrane normals. This tilt results from an interplay of the anchoring energy and rotational entropy of the complexes and facilitates the formation of receptor-ligand bonds at membrane separations smaller than the preferred separation for binding. In our simulations, we have considered both lipid-anchored and transmembrane receptor and ligand proteins. We find that the binding equilibrium constant and binding on-rate constant of lipid-anchored proteins are considerably smaller than the binding constant and on-rate constant of rigid transmembrane proteins with identical binding domains.