Evolution of Centrality Measurements for the Detection of Essential Proteins in Biological Networks.

Abstract

Current breakthroughs in high-throughput technologies have propelled the development of databases that systematically store knowledge of how genes, proteins, and metabolites interact. To elucidate the mechanisms of molecular interaction, such data can be represented through networks where nodes are biological entities (e.g., gene, protein, miRNA, transcription factor, and metabolites) and edges are associations/interactions between them (e.g., co-expression, signaling, regulation, and physical interaction). One approach to use such networks is to analyze their topological structure and try to relate this to biological function. Topological analysis hints at the possible behavior of a network in the regulation of biological processes or phenotypes and help in unveiling the core mechanisms. Broadly speaking, topological parameters can be used to explore: (1) collective behaviors (global properties such as diameter, small-world and scale-free properties of a network), (2) subnetwork behaviors (functional motif discovery), and (3) individual behaviors (prioritization of important nodes by centrality indices) of various network components (Ma and Gao, 2012). One of the first attempts found in the literature considered centrality related to lethality, and is known as the centrality–lethality rule proposed by Jeong et al. indicating a positive correlation between connectivity and indispensability in the yeast protein-protein interaction map (Jeong et al., 2001). Similarly, Wagner and Fell analyzed the structure of a large metabolic network of E. coli using metabolite node degree and shortest mean path length and observed small world like properties that follow power-law distributions (Wagner and Fell, 2001). In these two comprehensive studies, an old metric system (centrality index) was applied with different strategies, aiming to answer the following question: Do centrality indices predict the essential nodes in the biological networks? Remarkably, topological analyses carried out in transcriptional regulatory (TR) and metabolic networks have been a valuable guide to identify those biological components, called essential nodes, that play a major role in vital functional activities for some microorganisms (Resendis-Antonio et al., 2005, 2012). The relationship between nodes topological features, such as their degree, and their essentiality remains however debated (Coulomb et al., 2005). Prediction of essential proteins is a challenging task because it needs experimental approaches that are expensive, time-consuming, and laborious (Zhong et al., 2013; Li et al., 2014). To optimize the search of essential nodes in biological networks, a series of computational methods that include topological criteria have been proposed. In this paper, we review the cutting edge computational methods by categorizing them according to their underlying strategies to identify essential components. In each case, we discuss their predictive experimental power and identify shortcomings.