Protein Oligomerization Through Domain Swapping: Role of Inter-molecular Interactions and Protein Concentration - Aggregation & Cleavage

Protein Oligomerization Through Domain Swapping: Role of Inter-molecular Interactions and Protein Concentration
9 September 2005
Sichun Yang, Herbert Levine and Jos? N. Onuchic
Journal of Molecular Biology
Abstract
Domain swapping has been shown to be an important mechanism controlling multiprotein assembly and has been suggested recently as a possible mechanism underlying protein aggregation. Understanding oligomerization via domain swapping is therefore of theoretical and practical importance. By using a symmetrized structure-based (Go) model, we demonstrate that in the free-energy landscape of domain swapping, a large free-energy barrier separates monomeric and domain-swapped dimeric configurations. We investigate the effect of finite monomer concentration, by implementing a new semi-analytical method, which involves computing the second virial coefficient, a thermodynamic indicator of inter-molecular interactions. This method, together with the symmetrized structure-based (Go) model, minimizes the need for expensive many-protein simulations, providing a convenient framework to investigate concentration effect. Finally, we perform direct simulations of domain-swapped trimer formation, showing that this modeling approach can be used for higher-order oligomers.
Keywords: domain swapping; protein oligomerization; protein concentration; second virial coefficient; protein aggregation
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