A dual controllability analysis of influenza virus-host protein-protein interaction networks for antiviral drug target discovery

Ackerman, Emily E.; Alcorn, John F.; Hase, Takeshi; Shoemaker, Jason E.

Driver proteins (nodes) are the foundation of both types of controllability calculations, representing the protein set which must be manipulated for the system to be fully controlled. The proteins are identified through maximum matching algorithms [36] . The HIN and VIN both require N D = 2463 driver proteins to achieve controllability, suggesting that the magnitude of network control is unchanged by the influence of the IAV interactions. However, the identity of driver proteins shifts slightly as the 11 viral proteins replace 11 host proteins within the primary MIS as drivers in the VIN. Table 1 lists the identities of the 11 host proteins along with the shortest distance to an IAV protein in the network, degree, and betweenness. Of these 11 proteins, only five are directly interacting with IAV proteins. One of the remaining proteins is two steps (two interactions and one connecting protein) from any IAV protein, and the remaining five proteins are three steps from any IAV protein. The number of paths between viral proteins and these proteins are reflective of the number of paths between viral proteins and all host proteins (Fisher test p: 0.99). This supports the idea that viral interactions have lasting effects on the a b Fig. 2 a Degree of the VIN vs degree of the HIN where the IAV interacting proteins are marked in blue. The degree distributions of the networks are scale free. b Difference in betweenness between the VIN and HIN for proteins which exhibit a difference greater than one system's control structure, affecting proteins that are multiple paths away. Lastly, analysis finds that 8.9% of all driver proteins are also IAV interacting proteins, meaning the intersection of the two protein groups of interest comprise only 3.5% of the total network. There is a significant increase in the betweenness of driver proteins depending on their status as IAV interacting or IAV non-interacting proteins (Fisher test p < 2.2 × 10 − 16 ) where there is no significant difference in degree of the same groups (Fisher test p: 0.7161). This is further evidence that the addition of virus interactions to the network magnifies information flow through the proteins most involved in controlling network behavior.