  Some dimeric proteins first fold and then dimerize (three--state dimers)
while others first dimerize and then fold (two--state dimers). Within the
framework of a minimal lattice model, we can distinguish between sequences
obeying to one or to the other mechanism on the basis of the partition of the
ground state energy between bulk than for interface contacts. The topology of
contacts is very different for the bulk than for the interface: while the bulk
displays a rich network of interactions, the dimer interface is built up a set
of essentially independent contacts. Consequently, the two sets of interactions
play very different roles both in the the folding and in the evolutionary
history of the protein. Three--state dimers, where a large fraction of the
energy is concentrated in few contacts buried in the bulk, and where the
relative contact energy of interface contacts is considerably smaller than that
associated with bulk contacts, fold according to a hierarchycal pathway
controlled by local elementary structures, as also happens in the folding of
single--domain monomeric proteins. On the other hand, two--state dimers display
a relative contact energy of interface contacts which is larger than the
corresponding quantity associated with the bulk. In this case, the assembly of
the interface stabilizes the system and lead the two chains to fold. The
specific properties of three--state dimers acquired through evolution are
expected to be more robust than those of two--state dimers, a fact which has
consequences on proteins connected with viral diseases.
