  The last decade has witnessed a swiftly increasing interest in the design and
production of novel multivalent molecules as powerful alternatives for
conventional antibodies in the fight against cancer and infectious diseases.
However, while it is widely accepted that large-scale flexibility ($10-100$ nm)
and free/constrained dynamics (100 ns $- \mu$s) control the activity of such
novel molecules, computational strategies at the mesoscale still lag behind
experiments in optimizing the design of crucial features, such as the binding
cooperativity (a.k.a. avidity).
  In this study, we introduced different coarse-grained models of a
polymer-linked, two-nanobody composite molecule, with the aim of laying down
the physical bases of a thorough computational drug design protocol at the
mesoscale. We show that the calculation of suitable potentials of mean force
allows one to apprehend the nature, range and strength of the thermodynamic
forces that govern the motion of free and wall-tethered molecules. Furthermore,
we develop a simple computational strategy to quantify the
encounter/dissociation dynamics between the free end of a wall-tethered
molecule and the surface, at the roots of binding cooperativity. This procedure
allows one to pinpoint the role of internal flexibility and weak non-specific
interactions on the kinetic constants of the NB-wall encounter and
dissociation. Finally, we quantify the role and weight of rare events, which
are expected to play a major role in real-life situations, such as in the
immune synapse, where the binding kinetics is likely dominated by fluctuations.
