Structural dynamics of influenza A (H1N1) hemagglutinin protein: a comparative study of Indian (2018) isolate with its evolutionary neighbor, Californian (2009) strain.

This work highlights the structure and dynamics of two trimeric HA proteins of the H1N1 virus from different origins, the pandemic Californian (HACal) and its closest Indian neighbor (HAInd), reported in 2009 and 2018, respectively. Because of mutation, HAInd acquires new N-glycosylation and epitope binding sites along with mutations at RBD, which might trigger an altered viral-host interaction mechanism. Molecular dynamics simulations performed on HA trimers for a period of 250 ns reveal the highly dynamic nature of HACal trimers inherited by the flexibility of HA monomers. In the trimer, the dynamics of one monomer are more pronounced compared to others, and the enhanced dynamics of RBD especially gain attention as they plays a key role during fusion. Conversely, the mutant HAInd trimer effectively establishes more H-bond interactions, and accordingly, the trimer undergoes more stabilized dynamics with a relatively lower amplitude of RBD dynamics, as endorsed by the reduced RMSD, Rg, and SASA variations. The cooperative and anti-cooperative motions dissected for the subdomains of both strains also reveal a prominent anticorrelative motion of RBD against other subdomains. In agreement, the free energy landscape of stable HAInd is also characterized by a single lowest wide energy basin instead of the two minimum energy basins of the HACal trimer. In essence, the mutant HAInd acquires a highly stable conformation with novel functional features, which calls for (i) further investigation on the emerging mutation-mediated variation in viral-host binding mechanism and (ii) the need for further design of site-specific potential inhibitors to face future challenges.Communicated by Ramaswamy H. Sarma.

Structural dynamics of the RNA dependent RNA polymerase of H1N1 strain affecting humans: a bioinformatics approach.

The Influenza flu is a pandemic disease that renders the highest risk factor to the society due to its efficient ability of airborne transmission. Studies on the H1N1 strain gained significant focus, since its pandemic outbreak in 2009 and particularly the computational studies on its structural elements significantly aided in revealing their functional uniqueness. Among the 10 structural proteins of H1N1, the RNA-dependent RNA polymerase (RdRp) heterotrimeric protein complex, which is responsible for the synthesis of viral RNA (vRNA) from the negative-sense RNA genome of the virus, is the focus of the present study. This study aimed to investigate the structural dynamics of the RdRp complex with particular emphasis on the reported 17 mutations. The mutant strain is more stabilized by strong concerted residue-residue interactions at both intra- and inter- monomeric levels. In comparison, the mutant strain is structurally flexible with enhanced stabilizing interactions. The structural dynamics of RdRp are significantly governed by the dynamics of the (i) endonuclease domain of PA, (ii) RNA-entry region of PB1 and (iii) cap-binding region of PB2. Explicitly, the cap binding region of PB2 expresses (i) a concerted motion with the RNA-entry region, along with (ii) an anti-correlated motion with the endonuclease domain of the PA subunit, which further supports the stable dynamics of cap-binding towards RNA binding. These findings contribute to the understanding of the structural dynamics associated with the pandemic and mutant structures of RdRp and render a basic knowledge for further development of novel inhibitors towards influenza flu affected humans.Communicated by Ramaswamy H. Sarma.

Evolution of Indian Influenza A (H1N1) Hemagglutinin Strains: A Comparative Analysis of the Pandemic Californian HA Strain.

The need for a vaccine/inhibitor design has become inevitable concerning the emerging epidemic and pandemic viral infections, and the recent outbreak of the influenza A (H1N1) virus is one such example. From 2009 to 2018, India faced severe fatalities due to the outbreak of the influenza A (H1N1) virus. In this study, the potential features of reported Indian H1N1 strains are analyzed in comparison with their evolutionarily closest pandemic strain, A/California/04/2009. The focus is laid on one of its surface proteins, hemagglutinin (HA), which imparts a significant role in attacking the host cell surface and its entry. The extensive analysis performed, in comparison with the A/California/04/2009 strain, revealed significant point mutations in all Indian strains reported from 2009 to 2018. Due to these mutations, all Indian strains disclosed altered features at the sequence and structural levels, which are further presumed to be associated with their functional diversity as well. The mutations observed with the 2018 HA sequence such as S91R, S181T, S200P, I312V, K319T, I419M, and E523D might improve the fitness of the virus in a new host and environment. The higher fitness and decreased sequence similarity of mutated strains may compromise therapeutic efficacy. In particular, the mutations observed commonly, such as serine-to-threonine, alanine-to-threonine, and lysine-to-glutamine at various regions, alter the physico-chemical features of receptor-binding domains, N-glycosylation, and epitope-binding sites when compared with the reference strain. Such mutations render diversity among all Indian strains, and the structural and functional characterization of these strains becomes inevitable. In this study, we observed that mutational drift results in the alteration of the receptor-binding domain, the generation of new variant N-glycosylation along with novel epitope-binding sites, and modifications at the structural level. Eventually, the pressing need to develop potentially distinct next-generation therapeutic inhibitors against the HA strains of the Indian influenza A (H1N1) virus is also highlighted here.

Ebolabase: Zaire ebolavirus-human protein interaction database for drug-repurposing.

Ebola Virus (EBOV) is one of the deadliest pathogenic virus which causes hemorrhagic fever. Though many Ebola-human interaction studies and databases are already reported, the unavailability of an adequate model and lack of publically accessible resources requires a comprehensive study to curate the Ebola-Human-Drug interactions. In total, 270 human proteins interacted with EBOV are collected from published experimental evidence. Then the protein-protein interaction networks are generated as EBOV-human and EBOV-Human-Drugs interaction. These results can help the researcher to find the effective repurposed drug for EBOV treatment. Further, the illustration of gene enrichment and pathway analysis would provide knowledge and insight of EBOV-human interaction describes the importance of the study. Investigating the networks may help to identify a suitable human-based drug target for ebola research community. The inclusion of an emerging concept, a human-based drug targeted therapy plays a very significant role in drug repurposing which reduces the time and effort is the highlight of the current research. An integrated database namely, Ebolabase has been developed and linked with other repositories such as Epitopes, Structures, Literature, Genomics and Proteomics. All generated networks are made to be viewed in a customized manner and the required data can be downloaded freely. The Ebolabase is available at http://ebola.bicpu.edu.in.

Understanding of Zaire ebolavirus-human protein interaction for drug repurposing.

The Ebola virus is a human aggressive pathogen causes Ebola virus disease that threatens public health, for which there is no Food Drug Administration approved medication. Drug repurposing is an alternative method to find the novel indications of known drugs to treat the disease effectively at low cost. The present work focused on understanding the host-virus interaction as well as host virus drug interaction to identify the disease pathways and host-directed drug targets. Thus, existing direct physical Ebola-human protein-protein interaction (PPI) was collected from various publicly available databases and also literature through manual curation. Further, the functional and pathway enrichment analysis for the proteins were performed using database for annotation, visualization, and integrated discovery and the enriched gene ontology biological process terms includes chromatin assembly or disassembly, nucleosome organization, nucleosome assembly. Also, the enriched Kyoto Encyclopedia of Genes and Genome pathway terms includes systemic lupus erythematosus, alcoholism, and viral carcinogenesis. From the PPI network, important large histone clusters and tubulin were observed. Further, the host-virus and host-virus-drug interaction network has been generated and found that 182 drugs are associated with 45 host genes. The obtained drugs and their interacting targets could be considered for Ebola treatment.