Molecular mechanism of domain swapping in proteins: an analysis of slower motions.

Domain swapping is a structural phenomenon that plays an important role in the mechanism of oligomerization of some proteins. The monomer units in the oligomeric structure become entangled with each other. Here we investigate the mechanism of domain swapping in diphtheria toxin and the structural criteria required for it to occur by analyzing the slower modes of motion with elastic network models, Gaussian network model and anisotropic network model. We take diphtheria toxin as a representative of this class of domain-swapped proteins and show that the domain, which is being swapped in the dimeric state, rotates and twists, in going from the "open" to the "closed" state, about a hinge axis that passes through the middle of the loop extending between two domains. A combination of the intra- and intermolecular contacts of the dimer is almost equivalent to that of the monomer, which shows that the relative orientations of the residues in both forms are almost identical. This is also reflected in the calculated B-factors when compared with the experimentally determined B-factors in x-ray crystal structures. The slowest modes of both the monomer and dimer show a common hinge centered on residue 387. The differences in distances between the monomer and the dimer also shows the hinge at nearly the same location (residue 381). Finally, the first three dominant modes of anisotropic network model together shows a twisting motion about the hinge centered on residue 387. We further identify the location of hinges for a set of another 12 domain swapped proteins and give the quantitative measures of the motions of the swapped domains toward their "closed" state, i.e., the overlap and correlation between vectors.