Identification of important interacting proteins (IIPs) in Plasmodium falciparum using large-scale interaction network analysis and in-silico knock-out studies

Abstract

Background: Plasmodium falciparum causes the most severe form of malaria and affects 3.2 million people annually. Due to the increasing incidence of resistance to existing drugs, there is a growing need to discover new and more effective drugs against malaria. Despite the global importance of P. falciparum, vast majority of its proteins are uncharacterized experimentally. Application of newer approaches using several "omics" data has become successful for exploring the biological interactions underlying cellular processes. Till date not many system level study has been published using P. falciparum protein protein interaction. Hence, the purpose of this study is to develop a standardized pipeline for structural, functional, and topographical analysis of large scale protein protein interaction network (PPIN) in order to identify proteins important for network topology and integrity. Here, P. falciparum PPIN has been utilized as a model for better understanding of the molecular mechanisms of survival and pathogenesis of malaria parasite. Methods: Various graph theoretical approaches were implemented to identify highly interacting hub and central proteins that are crucial for network integrity. Further, potential network perturbing proteins via an in-silico knock-out (KO) analysis to isolate important interacting proteins (IIPs), which in principle, can elicit significant impact on the global and local environments of the P. falciparum interaction network Results: 177 hubs and 132 central proteins were identified from the malarial (proteins: 1607; interactions: 4750) PPI networks. Using the in-silico knock-out exercise 131 and 99 global and local network perturbing proteins were also identified. Finally, 271 proteins from P. falciparum were shortlisted as important interacting proteins (IIPs), which not only play crucial role in intra-pathogen network integrity, stage specificity but also interact with various human proteins involved in multiple metabolic pathways within the host cell. These IIPs could be used as potential drug targets in malarial research. Conclusion: Graph theoretical analysis of PPIN can be a very useful approach to identify proteins that are important for regulation of the interactions required for an organism's survival. Important interacting proteins (IIPs) identified using P. falciparum PPIN provides a useful dataset containing probable candidates for future drug target analysis.