Folding and Self-Assembly of a Small Protein Complex

The synthetic homotetrameric beta beta alpha (BBAT1) protein possesses a stable quaternary structure with a beta beta alpha fold. Because of its small size (a total of 84 residues), the homotetramer is an excellent model system with which to study the self-assembly and protein protein interactions. We find from replica exchange molecular dynamics simulations with the coarse-grain UNRES force field that the folding and association pathway consists of three well-separated steps, where association to a tetramer precedes and facilitates folding of the four chains. At room temperature, the tetramer exists in an ensemble of diverse structures. The crystal structure becomes energetically favored only when the molecule is in a dense and crystal-like environment. The observed picture of folding promoted by association may mirror the mechanism according to which intrinsically unfolded proteins assume their functional structures.