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      The Influenza-A mystery: Insight from Bioinformatics resources and analysis

      research-article
      Bioinformation
      Biomedical Informatics

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          Abstract

          Sir, Bioinformatics is a tool which can excavate any information, one wants to obtain. I found its implication in handling an emerging and highly pathogenic strain of Influenza virus, H5N1. The first influenza pandemic was happened in 1918 “Spanish flu” followed by Asian flu in 1957 caused by H2N2. Moreover, one million deaths were reported in Hong Kong due to H3N2 outbreak during 1968. The antigenic shift and drift of influenza A virus led to a new strain H1N1 in 1977 “Russian flu”. After two decades a new strain, H5N1 was evolved, called avian influenza virus. The outbreaks of this strain were continued till 2008 with the yearly epidemic in the world. In 2009, WHO has declared Influenza pandemic due to the outbreak of H1N1. The disease has infected over 35928 people in 80 countries, with 163 deaths. But it has been most severe in Mexico, which has reported the highest number of fatalities. The influenza virus is mysterious pathogen known for severe respiratory illness. It causes yearly epidemics in tropical and subtropical countries with epidemic and even pandemic flu, a major cause of morbidity and mortality. Recurrent appearance of influenza in different parts of the world is due to frequent mutations which may lead to either antigenic drift or shift. The structure of influenza A viral genome composed of eight segments of negative-sense single stranded RNA. Surface glycoprotein of influenza A virus, Hemagglutinin (HA) and Neuraminidase (NA) are the main components of viral genome to undergo reassortment and may cause to develop a new subtype or strain of Influenza virus. There are 16 different H antigens (H1 to H16) and nine different N antigens (N1 to N9). The latest H type (H16) was isolated from black-headed gulls found in Sweden and Netherlands during 1999 and was published in 2005. The history on influenza epidemic revealed circulation of these strains (H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3, H5N2 and H10N7) among human, pig and bird population of different regions on the globe [1]. The strains appeared during outbreaks in different parts of the world and with the gap of different time periods could be analyzed for their phylogeny to understand their origin or source of spread. Phylogenetic trees are built by Neighbour-joining program with Kimura 2 parameter available at phylip3.65 package [2]. It is drawn by using TreeView1.6 program [3]. We can further analyze genome using GOR IV method [4]. Different domains/motifs were searched by “Composite” available at Expasy server [5]. Moreover, Amino acids sequences are also compared by MAP MUTATION program [6] to analyze the mutations among these isolates. Homology modeling of template structure related to proteins was searched using Blast algorithms against PDB. Amino acids sequence of PB1-F2 protein of A/HK/156/97 was obtain from Swiss-Prot [ID: P0C0U0]. Homology modeling of PB1-F2 from A/HK/156/97 (H5N1) based on crystal structure of PB1-F2 protein [PDB id: 2HN8] from H1N1 subtypes with ≫69% identity, was built by modeler [7]. Rigid body docking of PB1-F2 protein with VDAC1 and ANT3 was performed by HEX5.1 [8,9]. Each docking solution was minimized by energy minimization technique. Details of interaction derived from refined structures were analyzed using the LIGPLOT program [10]. It is trouble-free as well as time saving to understand the insight of microbial genome to answer several hidden mysteries and therefore, the origin of viral strains during an outbreak, by exploring these tools can easily be identified. The viral genome databases, available on different sources, NCBI [11] and IVDB [12] could be used to retrieve the sequences for analysis.

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          LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions.

          The LIGPLOT program automatically generates schematic 2-D representations of protein-ligand complexes from standard Protein Data Bank file input. The output is a colour, or black-and-white, PostScript file giving a simple and informative representation of the intermolecular interactions and their strengths, including hydrogen bonds, hydrophobic interactions and atom accessibilities. The program is completely general for any ligand and can also be used to show other types of interaction in proteins and nucleic acids. It was designed to facilitate the rapid inspection of many enzyme complexes, but has found many other applications.
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            Evaluation of comparative protein modeling by MODELLER.

            We evaluate 3D models of human nucleoside diphosphate kinase, mouse cellular retinoic acid binding protein I, and human eosinophil neurotoxin that were calculated by MODELLER, a program for comparative protein modeling by satisfaction of spatial restraints. The models have good stereochemistry and are at least as similar to the crystallographic structures as the closest template structures. The largest errors occur in the regions that were not aligned correctly or where the template structures are not similar to the correct structure. These regions correspond predominantly to exposed loops, insertions of any length, and non-conserved side chains. When a template structure with more than 40% sequence identity to the target protein is available, the model is likely to have about 90% of the mainchain atoms modeled with an rms deviation from the X-ray structure of approximately 1 A, in large part because the templates are likely to be that similar to the X-ray structure of the target. This rms deviation is comparable to the overall differences between refined NMR and X-ray crystallography structures of the same protein.
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              Molecular interactions between mitochondrial membrane proteins and the C-terminal domain of PB1-F2: an in silico approach.

              PB1-F2 is a recently described influenza A viral protein that induces apoptosis by binding with two mitochondrial membrane proteins, i.e. VDAC1 (outer membrane) and ANT3 (inner membrane). Knowledge of this binding mechanism could provide insights that would aid in the design of novel inhibitors against this protein. Therefore, to better understand these interactions, we have undertaken this study to model the PB1-F2 protein of the highly pathogenic influenza A virus subtype H5N1. Moreover, a model of human ANT3 was also established. The dynamics of the molecular interactions between the C-terminal region of PB1-F2 protein and VDAC1 and ANT3 were expounded by employing an in silico approach. Our results suggest the involvement of 12 amino acids of PB1-F2 protein, which form hydrophobic contacts with 22 amino acids of VDAC1. Of these, Leu64, Arg75 and Val76 were found to be crucial for mitochondrial targetting. In the case of the PB1-F2-ANT3 complex, 14 amino acids of ANT3 were found to make hydrophobic contacts with 9 amino acids of PB1-F2. Furthermore, two hydrogen bonds were predicted in both complexes PB1-F2/VDAC1 and PB1-F2/ANT3. This study reveals the molecular interactions required for PB1-F2-induced apoptosis and suggests a hypothetical model for future study.
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                Author and article information

                Journal
                Bioinformation
                Bioinformation
                Bioinformation
                Biomedical Informatics
                0973-2063
                2009
                21 August 2009
                : 4
                : 1
                : 52
                Affiliations
                Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh 2020002, India
                Author notes
                [* ]Asad U Khan: asad.k@ 123456rediffmail.com ; Phone: +91-9837021912
                Article
                001000042009
                2770372
                20011154
                4ee1d9b3-303e-4bea-853c-965d253dcf51
                © 2009 Biomedical Informatics

                This is an open-access article, which permits unrestricted use, distribution, and reproduction in any medium, for non-commercial purposes, provided the original author and source are credited.

                History
                : 25 May 2009
                : 17 June 2009
                : 25 July 2009
                Categories
                Views & Challenges

                Bioinformatics & Computational biology
                Bioinformatics & Computational biology

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