Model for the evolution from type 3 to type 4 hemocyanin. Step (i) type 3 hemocyanin acquired FU-d* by gene duplication during evolution. FU-d* are entrapped on the sites that are thermodynamically stable, which correspond to FU-d* sites of conformer 1 and 2. Step (ii) Due to steric repulsion between FU-d*s, protomer dimers favor dissociation to monomers. Step (iii) Each dissociated monomer reassociates to form a homodimer, wherein domain swapping occurrs to avoid steric repulsion. Step (iv): Homodimers assemble circularly. Step (v) The dissociated monomers bind between the terminal subunits to close the circular association. Step (vi) FU-d*s rearrange to avoid steric repulsions and a hetero-protomer dimer is formed, which closes the circle.