  Proteins display generic properties that are challenging to explain by direct
selection, notably allostery, the capacity to be regulated through long-range
effects, and evolvability, the capacity to adapt to new selective pressures. An
evolutionary scenario is proposed where proteins acquire these two features
indirectly as a by-product of their selection for a more fundamental property,
exquisite discrimination, the capacity to bind discriminatively very similar
ligands. Achieving this task is shown to typically require proteins to undergo
a conformational change. We argue that physical and evolutionary constraints
impel this change to be controlled by a group of sites extending from the
binding site. Proteins can thus acquire a latent potential for allosteric
regulation and evolutionary adaptation because of long-range effects that
initially arise as evolutionary spandrels. This scenario accounts for the
groups of conserved and coevolving residues observed in multiple sequence
alignments. However, we propose that most pairs of coevolving and contacting
residues inferred from such alignments have a different origin, related to
thermal stability. A physical model is presented that illustrates this
evolutionary scenario and its implications. The scenario can be implemented in
experiments of protein evolution to directly test its predictions.
