Depletion Forces from Weakly Attractive Crowders

Macromolecular crowding is a key organizing principle in colloidal suspensions and biological systems where densely packed environments generate depletion forces that drive collective processes. Classical models like the Asakura-Oosawa (AO) theory capture purely entropic depletion but neglect the influence of weak interactions between nominally inert crowders, which are especially relevant in biological contexts. We have investigated the depletion potential of colloids immersed in Lennard-Jones crowders, which at modest crowder-crowder attraction leads to transient, correlated clusters, enhancing and extending the depletion range beyond classical AO predictions. We will present a cluster-weighted version of AO theory that treats clusters as effectively larger depletants. The depletion interaction range is determined by the cluster size distribution, while its magnitude depends on clustering dynamics captured by scaled virial coefficients. These theoretical predictions for the potential of mean force agree with enhanced sampling molecular dynamics simulations. Our findings highlight that crowder clustering controls depletion effects in systems with interacting crowders, offering a tractable route to describe effective interactions in interacting colloidal and biological systems.