Comparision of structural network between homologous proteins with variability derived from multiple conformers.

Abstract

Protein sequence determines its structure and hence its function. This indirect relationship between protein function and its structure lies deep rooted in the structural topology that has evolved into performance of optimal function. The evolution of structure and its interconnectivity have been studied predominantly using protein structure comparison metrics that quantify deviation from one another. A fundamental issue in computational structural biology is that the comparison of proteins by recruiting representative states of their structures is insufficient, as it does not account for their structural variability. We know how dynamic proteins are and it is necessary to include the variation in their topology while comparing them with their homologs. This fundamental issue is addressed here by looking into the alteration of inter-residue interactions across an ensemble of protein structure networks, instead of a single representative structure. A graph spectral comparison of the protein structural networks is employed to quantify the extent of dissimilarity in the structural topologies. We discuss in detail, scenarios where the variation of structure is not accompanied by loss or gain of overall network and its vice versa. Also, a newly obtained metric of topological change collated from the network dissimilarity score is used to obtain the phylogeny between the homologs and is compared with the sequence-based phylogeny. The method can also help to study the evolution of protein function based on the variation of their topologies.