Comparison of structural networks across homologous proteins

Protein sequence determines its structure and function. The indirect relationship between protein function and structure lies deep-rooted in the structural topology that has evolved into performing optimal function. The evolution of structure and its interconnectivity has been conventionally studied by comparing the root means square deviation between protein structures at the backbone level. Two factors that are necessary for the quantitative comparison of non-covalent interactions are (a) explicit inclusion of the coordinates of side-chain atoms and (b) consideration of multiple structures from the conformational landscape to account for structural variability. We have recently addressed these fundamental issues by investigating the alteration of inter-residue interactions across an ensemble of protein structure networks through a graph spectral approach. In this study, we have developed a rigorous method to compare the structure networks of homologous proteins, with a wide range of sequence identity percentages. A range of dissimilarity measures that show the extent of change in the network across homologous structures are generated, which also includes the comparison of the protein structure variability. We discuss in detail, scenarios where the variation of structure is not accompanied by loss or gain of the overall network and its vice versa. The sequence-based phylogeny among the homologs is also compared with the lineage obtained from information from such a robust structure comparison. In summary, we can obtain a quantitative comparison score for the structure networks of homologous proteins, which also enables us to study the evolution of protein function based on the variation of their topologies.