Analysis of core–periphery organization in protein contact networks reveals groups of structurally and functionally critical residues

Abstract

The representation of proteins as networks of interacting amino acids, referred to as protein contact networks (PCN), and their subsequent analyses using graph theoretic tools, can provide novel insights into the key functional roles of specific groups of residues. We have characterized the networks corresponding to the native states of 66 proteins (belonging to different families) in terms of their core-periphery organization. The resulting hierarchical classification of the amino acid constituents of a protein arranges the residues into successive layers - having higher core order - with increasing connection density, ranging from a sparsely linked periphery to a densely intra-connected core (distinct from the earlier concept of protein core defined in terms of the three-dimensional geometry of the native state, which has least solvent accessibility). Our results show that residues in the inner cores are more conserved than those at the periphery. Underlining the functional importance of the network core, we see that the receptor sites for known ligand molecules of most proteins occur in the innermost core. Furthermore, the association of residues with structural pockets and cavities in binding or active sites increases with the core order. From mutation sensitivity analysis, we show that the probability of deleterious or intolerant mutations also increases with the core order. We also show that stabilization centre residues are in the innermost cores, suggesting that the network core is critically important in maintaining the structural stability of the protein. A publicly available Web resource for performing core-periphery analysis of any protein whose native state is known has been made available by us at http://www.imsc.res.in/ ~sitabhra/proteinKcore/index.html.

The core decomposition of networks: theory, algorithms and applications

“…It turns out that in addition to the discovery of interesting correlations between connectivity and biological properties, the core/periphery structures help to reveal the existence of multiple levels of protein expression dynamics. Moreover, as reported in [73], residues belonging to inner cores are more conserved than those at the periphery of the network and also it seems that these groups are functionally and structurally critical. Another important result was reported in [44] which studied the relation between the core numbers of proteins and mutation rates.…”

Hierarchical closeness-based properties reveal cancer survivability and biomarker genes in molecular signaling networks

“…Therefore, we think that survival rate of a cancer patient is affected by two main factors: mutant position and signaling network structure. At a node level, mutations of a node at the innermost core are more deleteriously impactful than those at the rest of the network [ 17 , 23 , 76 ], thus such mutations may result in lower survival rates. At a network level, the network architecture with relatively high HC entropy results in lower cancer survival rates.…”

“…Core nodes are identified by pruning underutilized links until core-peripheries emerge [ 14 ] and play a differing role from peripheral nodes [ 15 , 16 ]. For example, in protein contact networks deleterious mutations which may cause cancer are more likely to be distributed near core nodes than peripheral nodes [ 17 ]. For instance, some prognostic genes of hepatocellular carcinoma, such as B1 and Sec62 , often reside at the core of gene co-expression networks [ 18 ].…”