Elucidation of conserved long-range interaction networks in proteins and their significance in determining protein topology

Investigations into the nature of sequence and structural conservation underlying protein folds have recently yielded profound insights into the mechanism of protein folding and stability. Combining this avenue of research with principles being pioneered in the field of network science holds the promise to further extend the boundaries of our knowledge. In this report we propose that critical determinants of a protein's native topology are encoded by a conserved network of interactions between amino acids from geographically important positions. This hypothesis is based on the novel elucidation of a conserved network of long-range interactions within a set of proteins that share a Greek-key topology and similar chain length, but differ in secondary structure composition, function and sequence. Exploratory macromolecular simulations using the conserved networks as constraints were successful in generating the gross native-like topology from a random linear coil for each of the model proteins. The results indicate that the conserved network contains governing features and supports the idea that the geographical location of these residue interactions is a pivotal feature underlying their conservation. The partially folded model proteins also display a clear scale-free distribution of long-range interactions. To further test the hypothesis, the network parameter betweeness-centrality was calculated for the protein structure networks of our model proteins and highlights two structural elements as particularly vital to the structural stability of the network topology.