Their role as global mediating nodes of long-range communications is less prominent and respectively their mutations have a smaller effect on the ATPase activity. We argue for the functional relevance of the centrality parameters as robust indicators of functionally important sites as this network analysis captured most of the known loss-of-function mutations. The organization of the interaction networks in the studied Hsp90-cochaperone complexes gives rise to smallworld networks, marked by a relatively small number of highly connected mediators occurring mostly at the intermolecular interfaces and playing critical roles in the transmission of functional signals. Small-world networks are characterized by small separation of nodes from each other, which for proteins means a higher degree of interaction cooperativity. The vulnerability of the interaction networks to targeted perturbations of highly connected hubs may explain why mutations of these critical hot spot residues could lead to a significant loss in chaperone activity. Complex networks may be either disassortative or assortative. In the network analysis, disassortativity produces better connected but more vulnerable networks, whereas assortativity gives rise to more resilient networks. We found that the interaction networks of the Hsp90cochaperone complexes may undergo a specific rewiring of key mediating residues and assortative Saikosaponin-C growth as a result of conformational equilibrium changes during protein-protein binding. Our results also suggested that the interaction networks may evolve the network of “supporting” residues that Tenuifoliside-C acquire sufficient communication capacity to pass signal from various central mediators across the network. The evolution of various networks has been extensively studied and 
a scale-free model of network organization has gained a considerable recognition. This model is based on the idea of “preferential attachment” where the most connected nodes are more likely to acquire new edges in the course of graph evolution. The scale-free topology of a network arises from network growth and preferential attachment endowing the network with high efficiency and robustness against random errors due to a small number of central nodes and exceedingly large number of peripheral nodes. However, due to the finite size of the protein structure graphs and topological constraints, the degree distribution of protein structure networks do not follow the preferential attachment scenario and is not scale-free, but is likely to be Poissonian. The fundamental reason for deviation from the scale-free behavior is the inherently limited interacting capacity of a given residue within a structural fold due to the excluded volume effect. The scale-free networks are highly efficient in transmitting long-range signal due short paths between any pair of nodes, but could be extremely vulnerable to targeted attacks on a few key hubs that could result in splitting the global network into smaller pieces. We suggest that protein structure networks may be more tolerant to targeted attacks at the expense of some efficiency by virtue of creating broad-scale connectivity in which global hubs and central mediators are often protected by a dense network of “secondary” hubs that could mitigate the effect of targeted mutations in certain functional sites. A possible explanation for the functional lethality of some, but not all, mediating residues is that assortative hubs are likely to be responsible for long-range communications that may be compromised by deleterious mutations. Although mutations of these residues may often result in a dramatic loss of activity, some of these alterations could be rescued by the presence of wellconnected supporting hubs that may assume “responsibility for global centrality”.