Construction of energy based Protein Structure Networks: application in the comparative analysis of Thermophiles and Mesophiles

Abstract

Thermophilic proteins sustain themselves and function at higher temperatures. Despite their structural and functional similarities with their mesophilic homologues, they show enhanced stability. Various comparative studies at genomic, protein sequence and structure levels, and experimental works highlight the different factors and dominant interacting forces contributing to this increased stability. In this comparative structure based study, we have used interaction energies between amino acids, to generate structure networks called as Protein Energy Networks (PENs). The interaction energy is the averaged sum of the Lennard-Jones and the Coulombic energies, over an equilibrium ensemble of conformations. The PENs are used to compute network parameters like largest connected component, clusters, cliques, communities and hubs. These parameters are then compared between the thermophile-mesophile homologues. The results show an increased number of clusters and low energy cliques in thermophiles as the main contributing factors for their enhanced stability. Further more, we see an increase in the number of hubs in thermophiles. We also observe no community of electrostatic cliques forming in PENs of both thermophiles and mesophiles. In summary, we have developed protein structure networks based on non-covalent interaction energies between amino acids. These networks are then exploited to identify the factors responsible for enhanced stability of thermophilic proteins, by comparative analysis. We were able to point out that the sub-graph parameters are the prominent contributing factors and also that the thermophilic proteins have a better packed hydrophobic core. We have also discussed how thermophilic proteins, although increasing stability through higher connectivity, retain conformational flexibility, from a cliques and communities perspective.