Open interface and large quaternary structure movements in 3D domain swapped proteins: insights from molecular dynamics simulations of the C-terminal swapped dimer of ribonuclease A

Bovine pancreatic RNase (RNase A) forms two three-dimensional (3D) domain swapped dimers. Crystallog. investigations have revealed that these dimers display completely different quaternary structures: one dimer (N-dimer), which presents the swapping of the N-terminal helix, is characterized by a compact structure, whereas the other (C-dimer), which is stabilized by the exchange of the C-terminal end, shows a rather loose assembly of the two subunits. The dynamic properties of monomeric RNase A and of the N-dimer have been extensively characterized. Here, the authors report a mol. dynamics investigation carried out on the C-dimer. This computational expt. indicates that the quaternary structure of the C-dimer undergoes large fluctuations. These motions do not perturb the proper folding of the two subunits, which retain the dynamic properties of RNase A and the N-dimer. Indeed, the individual subunits of the C-dimer display the breathing motion of the b-sheet structure, which is important for the enzymic activity of pancreatic-like RNases. In contrast to what has been obsd. for the N-dimer, the breathing motion of the two subunits of the C-dimer is not coupled. This finding suggests that the intersubunit communications in a 3D domain swapped dimer strongly rely on the extent of the interchain interface. Furthermore, the observation that the C-dimer is endowed with a high intrinsic flexibility holds interesting implications for the specific properties of 3D domain swapped dimers. Indeed, a survey of the quaternary structures of the other 3D domain swapped dimers shows that large variations are often obsd. when the structural detns. are conducted in different exptl. conditions. The 3D domain swapping phenomenon coupled with the high flexibility of the quaternary structure may be relevant for protein-protein recognition, and in particular for the pathol. aggregations.