A Simple Model of Protein Domain Swapping in Crowded Cellular Environments

Abstract

Domain swapping in proteins is an important mechanism of functional and structural innovation. However, despite its ubiquity and importance, the physical mechanisms that lead to domain swapping are poorly understood. Here, we present a simple two-dimensional coarse-grained model of protein domain swapping in the cytoplasm. In our model, two-domain proteins partially unfold and diffuse in continuous space. Monte Carlo multiprotein simulations of the model reveal that domain swapping occurs at intermediate temperatures, whereas folded dimers and folded monomers prevail at low temperatures, and partially unfolded monomers predominate at high temperatures. We use a simplified amino acid alphabet consisting of four residue types, and find that the oligomeric state at a given temperature depends on the sequence of the protein. We also show that hinge strain between domains can promote domain swapping, consistent with experimental observations for real proteins. Domain swapping depends nonmonotonically on the protein concentration, with domain-swapped dimers occurring at intermediate concentrations and nonspecific interactions between partially unfolded proteins occurring at high concentrations. For folded proteins, we recover the result obtained in three-dimensional lattice simulations, i.e., that functional dimerization is most prevalent at intermediate temperatures and nonspecific interactions increase at low temperatures.

GRB2 dimerization mediated by SH2 domain-swapping is critical for T cell signaling and cytokine production

“…Given that Pro residues often occur in hinge loops and are important in the swapping process, we mutated Val122 and Val123 to Pro residues in order to generate a stable dimeric GRB2 construct (Fig. 1D) [77][78][79][80][81][82][83][84][85] . We hypothesized that the strain introduced into the loop by the Pro side chains would induce opening of the loop and lower the energetic barrier to SH2/SH2 domain-swapping.…”

Reducing discrepancies between 3D and 2D simulations due to cell packing density

“…This is justified when some dimensions may be considered as equivalent to each other, and when there is no need to consider navigation of fluids or objects around obstacles. Relevant examples where reduced dimensionality is assumed include smooth particle hydrodynamics of viscous media (Lu et al, 2005) and Monte Carlo simulations of protein interactions (Woodard et al, 2016).…”