Multivalent Recognition at Fluid Surfaces: The Interplay of Receptor Clustering and Superselectivity

The interaction between
a biological membrane and its environment
is a complex process, as it involves multivalent binding between ligand/receptor
pairs, which can self-organize in patches. Any description of the
specific binding of biomolecules to membranes must account for the
key characteristics of multivalent binding, namely, its unique ability
to discriminate sharply between high and low receptor densities (superselectivity),
but also for the effect of the lateral mobility of membrane-bound
receptors to cluster upon binding. Here we present an experimental
model system that allows us to compare systematically the effects
of multivalent interactions on fluid and immobile surfaces. A crucial
feature of our model system is that it allows us to control the membrane
surface chemistry, the properties of the multivalent binder, and the
binding affinity. We find that multivalent probes retain their superselective
binding behavior at fluid interfaces. Supported by numerical simulations,
we demonstrate that, as a consequence of receptor clustering, superselective
binding is enhanced and shifted to lower receptor densities at fluid
interfaces. To translate our findings into a simple, predictive tool,
we propose an analytical model that enables rapid predictions of how
the superselective binding behavior is affected by the lateral receptor
mobility as a function of the physicochemical characteristics of the
multivalent probe. We believe that our model, which captures the key
physical mechanisms underpinning multivalent binding to biological
membranes, will greatly facilitate the rational design of nanoprobes
for the superselective targeting of cells.