  Proteins need to selectively interact with specific targets among a multitude
of similar molecules in the cell. But despite a firm physical understanding of
binding interactions, we lack a general theory of how proteins evolve high
specificity. Here, we present such a model that combines chemistry, mechanics
and genetics, and explains how their interplay governs the evolution of
specific protein-ligand interactions. The model shows that there are many
routes to achieving molecular discrimination - by varying degrees of
flexibility and shape/chemistry complementarity - but the key ingredient is
precision. Harder discrimination tasks require more collective and precise
coaction of structure, forces and movements. Proteins can achieve this through
correlated mutations extending far from a binding site, which fine-tune the
localized interaction with the ligand. Thus, the solution of more complicated
tasks is enabled by increasing the protein size, and proteins become more
evolvable and robust when they are larger than the bare minimum required for
discrimination. The model makes testable, specific predictions about the role
of flexibility and shape mismatch in discrimination, and how evolution can
independently tune affinity and specificity. Thus, the proposed theory of
specific binding addresses the natural question of "why are proteins so big?".
A possible answer is that molecular discrimination is often a hard task best
performed by adding more layers to the protein.
