2025
PNAS

Reciprocity in dynamics of supramolecular biosystems for the clustering of ligands and receptors

Authors:

Shikha Dhiman, Marle E. J. Vleugels, Richard A. J. Post, Martina Crippa, Annalisa Cardellini, Esmee de Korver, Lu Su, Anja R. A. Palmans, Giovanni M. Pavan, Remco W. van der Hofstad, Lorenzo Albertazzi, E. W. Meijer

Keywords:

multivalency; supramolecular polymer; clustering; biomaterials; dynamics

Abstract:

Multivalent binding and the resulting dynamical clustering of receptors and ligandsare known to be key features in biological interactions. For optimizing biomaterialscapable of similar dynamical features, it is essential to understand the first step of theseinteractions, namely the multivalent molecular recognition between ligands and cellreceptors. Here, we present the reciprocal cooperation between dynamic ligands insupramolecular polymers and dynamic receptors in model cell membranes, determiningmolecular recognition and multivalent binding via receptor clustering. The nonlin-ear dependences of the ligand concentration, receptors, and their binding affinity areobserved experimentally by fluorescence and superresolution fluorescence microscopies,revealing a valency- dependent clustering mode of anchoring. The mechanism is sup-ported by stochastic modeling demonstrating that such nonlinear dependence is unlikelyin the absence of any dynamics and superselectivity. Using a coarse-grained molecularmodel, the subtle competition between local and global entropies that controls thisanchoring mechanism explains the clustering. Further investigation using single particletracking reveals the presence of two populations of bound and unbound receptors afterthe clustering process. The result of this study highlights the importance of reciprocityof dynamics in supramolecular polymer and lipid membrane for recruitment, multiva-lent binding, and clustering, all of which are crucial elements in the design of materialscapable of actively interacting with biological targets.