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.

Global controllability was calculated (see Methods) for all proteins of the HIN and VIN (as shown in Table 3 with and without parentheses, respectively). Unlike in robust controllability, there is a small disturbance to global type distributions of host proteins after the addition of virus interactions. 24 host proteins shift from being classified as critical (a member of all MISs) to intermittent (a member of some MISs) proteins. Identities of these proteins (deemed "global proteins") can be found in Table 4 along with the shortest distance to an IAV protein in the network and protein degree and betweenness. The two most notable changes in degree and betweenness between the HIN and VIN are EPH receptor A2 (EPHA2) with an increase of 1 and 93, respectively, and transferrin receptor (TFRC), with an increase of 3 and 164, respectively. All 24 global proteins are driver and IAV interacting proteins which, as mentioned, only comprises 3.5% of the total network. There are only two proteins (EPHA2 and HNRNPA0) that are also members of the robust protein set. 45% of IAV interacting proteins are never drivers, suggesting that they are always manipulated by neighboring host proteins within any possible control configuration. IAV interacting proteins are not enriched for driver proteins (Fisher test p: 0.14). Again, a randomized protein set was created to test if IAV may be selectively interacting with host proteins based on their controllability characteristics. 10,000 random sets of 752 proteins (the number of IAV interacting proteins) were sampled from the host proteins of the VIN. Their global type distributions were plotted against the classification results of IAV interacting proteins, driver proteins, and all proteins in the VIN (Fig. 3d-f ) . As with the robust classification, the random sets closely resemble the total network (one-sided p = 0.50, 0.51, and 0.50 for critical, intermittent, and redundant, respectively). While there are no redundant driver proteins by definition, driver proteins are more likely to be intermittent proteins than critical proteins (Fig. 3d-e) , where more than 75% of all driver proteins are missing from at least one possible MIS. This means the majority of possible driver proteins are able to be controlled by a neighboring protein in at least one MIS. IAV interacting proteins tend to be redundant compared to the total number of proteins that are redundant (Fig. 3f ) . This suggests that viruses prefer to interact with proteins that are part of existing control structures to receive input from neighboring proteins.