Domain swapping is a consequence of minimal frustration

Abstract

The same energy landscape principles associated with the folding of proteins into their monomeric conformations should also describe how these proteins oligomerize into domain-swapped conformations. We tested this hypothesis by using a simplified model for the epidermal growth factor receptor pathway substrate 8 src homology 3 domain protein, both of whose monomeric and domain-swapped structures have been solved. The model, which we call the symmetrized Gō-type model, incorporates only information regarding the monomeric conformation in an energy function for the dimer to predict the domain-swapped conformation. A striking preference for the correct domain-swapped structure was observed, indicating that overall monomer topology is a main determinant of the structure of domain-swapped dimers. Furthermore, we explore the free energy surface for domain swapping by using our model to characterize the mechanism of oligomerization.

Fig. 1.

Contact maps for Eps8 SH3 domain and the symmetrized Gō -type model. (a) The structure and contact map of MSH3 [Protein Data Bank (PDB) ID 1I0C] of Eps8. (b) The structure and contact map of DSH3 (PDB ID 1I07) of Eps8. (c) A schematic illustration for the symmetrized Gō -type model and the corresponding contact map for the two-chain system (see text for details). In this symmetrized Gō -type model contact map, red and blue represent all of the intrachain contacts for chains A and B, respectively. Green represents the native interchain contacts that are found in the domain-swapped structure of DSH3. Black represents the nonnative interchain contacts that are not found in the domain-swapped structure of DSH3. The structures were created with molscript (36).

Fig. 2.

The flexibility of the n-src hinge loop. (a) The dihedral angle difference for C^α atoms between MSH3 and DSH3 shows that the large conformational change for domain swapping is located at the flexible n-src loop (residues 35–39). (b) Higher thermal B-factors for C^α atoms in the n-src and distal loops of DSH3 [Protein Data Bank (PDB) ID 1I07].

Fig. 3.

Symmetrized Gō -type model with flexible loops. Shown is the contact probability map for Q_interchain > 100 (above diagonal line) and symmetrized contact map (below diagonal line) for the flexible n-src loop only (a), the flexible (partly) RT and n-src loops (b), and the flexible n-src and distal loops (c).

Fig. 4.

Symmetrized Gō -type model with relaxed dihedral force constants. Contact probability map for Q_interchain > 77 (above diagonal line) and contact map of the natively domain-swapped dimer (below diagonal line) from sets of simulated annealing molecular dynamics simulations. (a) Changes to the dihedral force constants and . (b) and .

Fig. 5.

Free energy landscapes for domain swapping as a function of Q_intrachain and Q_interchain at five temperatures of an eight-replica simulation with the interchain center-of-mass constraint and R₀ = 0.1r₀.