A Multi-Scale Model for the Assembling Kinetics of Protein Complexes

Abstract

The assembly of proteins into high-order complexes is a general mechanism for these biomolecules to implement their versatile functions in cells. Natural evolution has developed various assembling pathways for specific protein complexes to maintain their stability and proper activities. Previous studies show numerous examples that misassembly of protein complexes can lead to severe biological consequences. Although our research focus has started to be moved beyond the static representation to the dynamic aspect of protein quaternary structures, current understanding of the assembly mechanism of protein complexes is still largely limited. To tackle this problem, we developed a new multi-scale modeling framework. The framework combines a lower-resolution rigid-body-based simulation with a higher-resolution Cα-based simulation method, so that protein complex can be assembled with both structural details and computational efficiency. We applied the model to a homo-trimer and a hetero-tetramer as simple testing systems. Consistent with experimental observations, our simulations indicated very different kinetics between protein oligomerization and dimerization. The formation of protein oligomers is a multi-step process that is much slower than dimerization, but thermodynamically more stable. Moreover, we showed that even the same protein quaternary structure can have very diverse assembly pathways under different binding constants between subunit, which is a significant feature to regulate functions of protein complexes. Finally, we revealed that the binding between subunits in a complex can be synergistically strengthened during assembly without taking accounts of allosteric regulation or conformational changes. Therefore, our model provides a useful tool to understand the general principles of protein complex assembly.