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Computational studies of H5N1 hemagglutinin binding with SA-α-2, 3-Gal and SA-α-2, 6-

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  • Computational studies of H5N1 hemagglutinin binding with SA-α-2, 3-Gal and SA-α-2, 6-

    All thanks to my wife who is now PHD/PSYD student and have this access to university's suscribed scientific documentation library.



    _________________



    Computational studies of H5N1 hemagglutinin binding with SA-α-2, 3-Gal and SA-α-2, 6-Gal


    Minyong Li<sup>a</sup> and Binghe Wang<sup></sup><sup>, </sup><sup>a</sup><sup>, </sup><sup></sup>

    <sup>a</sup>Department of Chemistry and Center for Biotechnology and Drug Design, Georgia State University, Atlanta, GA 30302-4098, USA

    Received 18 June 2006. Available online 10 July 2006.



    Abstract

    For influenza H5N1 hemagglutinin, a switch from SA-α-2, 3-Gal to SA-α-2, 6-Gal receptor specificity is a critical step leading to the conversion from avian-to-human to human-to-human infection. Therefore, the understanding of the binding modes of SA-α-2, 3-Gal and SA-α-2, 6-Gal to H5N1 hemagglutinin will be very important for the examination of possible mutations needed for going from an avian to a human flu virus. Based on the available H5N1 hemagglutinin crystal structure, the binding profiles between H5N1 hemagglutinin and two saccharide ligands, SA-α-2, 3-Gal and SA-α-2, 6-Gal, were investigated by ab initio quantum mechanics, molecular docking, molecular mechanics, and molecular dynamics simulations. It was found that SA-α-2, 3-Gal has strong multiple hydrophobic and hydrogen bond interactions in its trans conformation with H5N1 hemagglutinin, whereas the SA-α-2, 6-Gal only shows weak interactions in a different conformation (cis type).
    Keywords: H5N1; Avian influenza; Neuraminidase; Hemagglutinin; Molecular docking; ab initio calculation; Molecular mechanics; Molecular dynamics



    Article Outline

    <dl><dt> Materials and methods</dt><dt> Results and discussion</dt><dl><dt> SA-α-2, 3-Gal-H5N1 HA complex analysis</dt><dt> SA-α-2, 6-Gal-H5N1 HA complex analysis</dt></dl><dt> Conclusion</dt><dt>Acknowledgements</dt><dt>References</dt></dl>


    The outbreak of H5N1 avian influenza virus, or commonly called ?bird flu,? is of a major health concern not only because of its high death rate [1], but also because of its highly contagious nature and its ability to mutate and develop resistance to known therapies [2]. The possibility of a human pandemic of H5N1 flu is not considered a remote possibility [3] if uncontrolled. Therefore, there is a great deal of interest in examining the various factors important for the transformation of a virus that primarily infects chicken to a strain that would pass from human to human.
    As one of the two principal antigens found on the influenza viral surface, hemagglutinin (HA) interact with host-cell receptors containing the terminal sialic acid (SA) residue [4]. Such interactions are responsible for viral binding to host cells, enabling cellular entry through endocytosis. Therefore, HA could be an important target for both drug and vaccine development [5]. SAs are usually found in either an α-2, 3 or an α-2, 6 linkage to galactose (Gal), the predominant penultimate sugar of N-linked carbohydrate side chains (Fig. 1) [6]. Human influenza viruses prefer SA-α-2, 6-Gal-linked saccharides, whereas avian influenza viruses prefer those terminating in SA-α-2, 3-Gal [7].


    Fig. 1. The chemical structures of SA-α-2, 3-Gal and SA-α-2, 6-Gal.
    Recently there have been several exciting investigations of H5N1 HA. One is the recognition that H5N1 virus with specificity for SA-α-2, 3-Gal would preferentially attach to the lower respiratory airway in human [8] and [9]. The other is the resolution of the crystal structure of HA derived from A/Vietnam/1203/2004 (H5N1) virus [10]. It is believed that a switch from α-2, 3 to α-2, 6 receptor specificity is a critical step in the adaptation of avian viruses to a human host, while α-2, 3 specificity alone appears to be one of the reasons that most avian influenza viruses, including current avian H5 strains, are not easily transmitted from human to human after avian-to-human infection [7] and [11]. Thus, the question that needs to be addressed is how a H5N1 virus could adapt its HA for binding with human receptor, SA-α-2, 3-Gal and SA-α-2, 6-Gal.
    In this study, we undertook the task of using computational methods to understand the binding of H5N1 HA to SA-α-2, 3-Gal and SA-α-2, 6-Gal. First of all, the ligands were built and optimized by ab initio calculation. Subsequently, the ligands were docked into the receptor site of the crystal structure of H5N1 HA. The complexes were then optimized by molecular mechanics and molecular dynamics approaches. Finally, the optimized complexes were analyzed in terms of ligand-HA interactions. The results from this study should allow for a better understanding of the binding mode of H5N1 HA with SA-α-2, 3-Gal and SA-α-2, 6-Gal. Such information should be very useful for understanding mutations that could lead to human infection and for the design of inhibitors that could block the binding of H5N1 virus to host cells.
    Materials and methods

    Modeling of SA-α-2, 3-Gal and SA-α-2, 6-Gal binding with HA. The ligands, SA-α-2, 3-Gal and SA-α-2, 6-Gal, were built and optimized at Hartree-Fock level with the 6-311 G basis set by Gaussian 03 program [12]. The optimized ligands were then embedded with Gastiger-H?ckel partial charge by SYBYL 7.1 package. For HA, the original crystallographic structure was used as a starting point (PDB entry: 2FK0) [10], with the addition of all missing hydrogen atoms and assignment of Kollman all-atom charges by SYBYL. Docking of the ligands into the HA receptor site was then performed by DOCK 5.4 program [13]. The docked complexes were solvated by using the TIP3P water model, subjected to 500-steps of molecular mechanics minimization and molecular dynamics simulations at 300 K for 1.5 ns using the SANDER module in AMBER 8 program [14]. The resultant structures were then analyzed using HBPLUS 3.06 [15] and Ligplot 4.22 [16] program to identify specific contacts between ligands and HA.
    Hardware and software. SYBYL 7.1 was used for molecular modeling on a SGI workstation. The ab initio optimization (Gaussian 03), molecular mechanics calculations, and molecular dynamics simulations (AMBER 8) were performed on a Linux-based 40-node cluster. The docking calculation (DOCK 5.4) and binding analysis (HBPLUS 3.06 and Ligplot 4.22) were carried out on a Linux workstation. The visualization of complexes was employed by Pymol 0.99 program [17] on a Windows XP workstation.
    Results and discussion

    SA-α-2, 3-Gal-H5N1 HA complex analysis

    Since H5N1 HA has an intrinsic preference for SA-α-2, 3-Gal [7] and [11], we first studied the binding of H5N1 HA with SA-α-2, 3-Gal. In doing so, the structure of SA-α-2, 3-Gal was first derived from ab initio calculations. This optimized SA-α-2, 3-Gal structure was docked into the binding site of H5N1 HA and then minimized using both molecular dynamics and molecular mechanics in the TIP3P soaked model. The schematic analysis of SA-α-2, 3-Gal-H5N1 HA complex shows the residues involved in receptor site as seen in Fig. 2. The docking conformation of SA-α-2, 3-Gal around the receptor binding domain of H5N1 HA is depicted in Fig. 3. In the optimized structure, SA-α-2, 3-Gal adopted a U-shape with the two monosaccharides in a trans orientation (for cis and trans definition, see Fig. 1). On the whole SA-α-2, 3-Gal has possible strong hydrophobic interaction with seven amino acid residues, Ser 136, Trp 153, Ile 155, His 183, Glu 190, Leu 194, and Gln 226, as judged by the HBPLUS program [15]. Moreover, analysis with the HBPLUS program suggests that SA-α-2, 3-Gal can form 11 strong hydrogen bonds with Tyr 98, Val 135, Ser 136, Ser 137, His 183, Glu 190, and Gln 226. The trans conformation of SA-α-2, 3-Gal directs the Gal ring somewhat away from the receptor binding domain surface. As a result, there is only partial interaction of the Gal moiety with the receptor. However, there is a strong hydrogen bond between the axial 4-hydroxyl group of Gal and the important Gln 226 residue (carbonyl oxygen), which is also involved in hydrogen bond interactions with the 1-carboxylate and 2-glycerol hydroxyl group of SA. Our results are consistent with what has been proposed based on experiments, i.e., Gln 226 is a very critical residue involved in H5N1 HA receptor binding [18]. Overall, the results indicate that SA-α-2, 3-Gal have strong interactions and thus binding with H5N1 HA, which are consistent with experimental results [8] and [9].

    <table border="0" width="100%"><tbody><tr><td align="right" height="25" width="100%"></td> </tr> <tr><td bgcolor="#8cc919" height="2" width="100%">
    </td></tr> </tbody></table>

    Fig. 2. A schematic illustration of the interactions of SA-α-2, 3-Gal with the residues around the receptor site of H5N1 hemagglutinin.
    <table border="0" width="100%"><tbody><tr><td align="right" height="25" width="100%"></td> </tr> <tr><td bgcolor="#8cc919" height="2" width="100%">
    </td></tr> </tbody></table>

    Fig. 3. The docking conformation of SA-α-2, 3-Gal into the receptor site of H5N1 hemagglutinin. The ligand, SA-α-2, 3-Gal, is shown in sticks and the important residues around the receptor site surface are shown in lines.

    SA-α-2, 6-Gal-H5N1 HA complex analysis

    Similar to the case of SA-α-2, 3-Gal-H5N1 studies, the initial conformation of SA-α-2, 6-Gal was derived from ab initio calculations. This structure was then docked into the receptor binding site of H5N1 HA. The minimized structure of the complex showed SA-α-2, 3-Gal in a similar general orientation as compared with SA-α-2, 3-Gal. Furthermore, compared with the trans conformation of SA-α-2, 3-Gal, one most prominent feature is that SA-α-2, 6-Gal adopts a cis conformation. The hydrophobic interactions of SA-α-2, 6-Gal-HA complex were less prominent compared with the SA-α-2, 3-Gal complex showing weak hydrophobic contacts with only three residues, Trp 153, Ile 155, and Glu 190, of H5N1 HA, as judged by the HBPLUS program. There are also three hydrogen bonds (one fairly weak with a distance of 3.54 Ŵ) identified involving the equatorial 1-hydroxyl group of the Gal ring and the amide motif of SA with three residues, Leu 133, Val 135, and Lys 193, of H5N1 HA. This weak interaction profile is consistent with experimental results [8] and [9]. Fig. 4 schematically reports the main interactions between SA-α-2, 6-Gal and H5N1 HA. Fig. 5 presents the conformation of SA-α-2, 6-Gal docked into H5N1 HA receptor site, in which the SA-α-2, 6-Gal moiety is pushed further away from the receptor site than does the 3-Gal moiety in SA-α-2, 3-Gal (Fig. 6). Such results shed light on the difference in specific interactions between H5N1 HA and SA-α-2, 3-Gal and SA-α-2, 6-Gal.
    <table border="0" width="100%"><tbody><tr><td bgcolor="#8cc919" height="2" width="100%">
    </td></tr> </tbody></table>

    Fig. 4. A schematic illustration of the interactions of SA-α-2, 6-Gal with residues around the receptor site of H5N1 hemagglutinin.


    Fig. 5. The docking conformation of SA-α-2, 6-Gal into the receptor site of H5N1 hemagglutinin. The ligand, SA-α-2, 6-Gal, is shown in sticks and the important residues around the receptor site surface are shown in lines.



    Fig. 6. The superimposition of SA-α-2, 3-Gal (green-based sticks) and SA-α-2, 6-Gal (blue-based sticks) around the receptor binding domain (blue box) of H5N1 hemagglutinin. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this paper.)
    To correlate the computational outcome with available experimental results, we have compared the computational structures with available NMR and/or crystal structures of the sugars and HA-sugar complex. There have been NMR studies of the SA-α-2, 6-Gal structural moiety. It has been found that the α-2, 6 linkage is predominantly in a cis conformation in aqueous solution with a cis:trans ratio of 9:1 when determined by NMR spectroscopy and Monte Carlo simulation [19]. For SA-α-2, 6-Gal, the molecular docking into H5N1 HA and the subsequent optimization led to a cis conformation with high similarity to that of the NMR results. This cis conformation in its complex with H5N1 HA puts the C<sub>2</sub> atom of the Gal ring in a position that blocks hydrogen bond formation with Gln 226, thus leaving only weak hydrophobic interactions between SA and the receptor binding domain surface of HA (Fig. 5).
    H9N2 is an avian flu virus. The crystal structure of H9N2 HA complexed with LSTc (PDB entry: 1JSI) [20], which has the SA-α-2, 6-Gal linkage, has been reported. We were interested in examining how our computational results compared with the crystal structural results, especially with regard to the SA-α-2, 6-Gal moiety. Thus, the SA-α-2, 6-Gal-H5N1 HA complex was superimposed with the H9N2-HA-LSTc complex to compare the difference in interaction profiles. It needs too be noted that LSTc can be sensitively recognized by human H1 HA, but it bears low affinity with swine H9 HA [20] and [21]. After superimposition, the binding patterns between SA-α-2, 6-Gal-H5N1 HA and LSTc-H9N2 HA showed great similarity, especially with regard to the cis conformations of SA-α-2, 6-Gal motifs (Fig. 7).
    <table border="0" width="100%"><tbody><tr><td bgcolor="#8cc919" height="2" width="100%">
    </td></tr> </tbody></table>

    Fig. 7. Structural comparison of swine H9N2 HA (blue ribbon) and avian H5N1 HA (green ribbon) binding with SA-α-2, 6-Gal-linked saccharides, LSTc (yellow stick), and SA-α-2, 6-Gal (red stick). (A) Overview. (B) The superimposition of LSTc and SA-α-2, 6-Gal around the receptor binding domain generated through computation. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this paper.)
    In H5N1 there are a number of conserved residues involved in receptor binding, such as Tyr 98, Trp 153, and His 183 [22]. Recent mutation analysis and glycan microarray analysis identified some critical residues involved in binding, such as Glu 190 and Gln 226 [10]. Our computational investigation indicates that SA-α-2, 3-Gal has strong interactions with Tyr 98, Trp 153, His 183, Glu 190, and Gln 226 around the receptor site of HA. All these are also very consistent with experimental results as to the importance of certain selected residues [8] and [9].
    Overall, the computational results have identified specific interactive functional groups between the carbohydrates and H5N1 HA that are consistent with the general preference of H5N1 HA for SA-α-2, 3-Gal. All the conformational features derived from computation are consistent with experimental results whenever available and the specific interactions identified are consistent with experimental mutational results. Such general agreement between the computational and experimental results further supports the validity of the important binding features identified in our computational effort.
    Conclusion

    In summary, we have determined how the SA-α-2, 3-Gal and SA-α-2, 6-Gal bind with H5N1 HA using ab initio quantum calculation, molecular docking, molecular mechanics, and molecular dynamics simulation. Given the results presented in this report, it indicates that the SA-α-2, 3-Gal-HA complex has strong multiple hydrophobic and hydrogen bond interactions whereas the SA-α-2, 6-Gal-HA complex only shows weak interactions. Most of the difference arise from the cis conformation of the SA-α-2, 6-Gal, which resulted in the Gal ring of SA-α-2, 6-Gal being pushed away from interactions with residue Gln 226, which are prominently involved in interactions with SA-α-2, 3-Gal. These computational results are consistent with available experimental studies. This characterization of the H5N1 receptor site could be used in the future as a starting point to analyze the dynamic behavior of ligand interaction, to understand the infection mechanism of avian influenza virus, and to design novel inhibitors of H5N1 HA for the treatment of avian flu.



    Acknowledgments

    Financial support from the Georgia Cancer Coalition, Georgia Research Alliance, and the National Institutes of Health (CA123329, CA113917) is gratefully acknowledged. The authors thank Dr. James Stevens and Dr. Ian Wilson (Department of Molecular Biology, The Scripps Research Institute) for their in advance X-ray structure of H5N1 hemagglutinin.



    References

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  • #2
    Re: Computational studies of H5N1 hemagglutinin binding with SA-α-2, 3-Gal and SA-α-2, 6-

    I wished I would better understand the implications of this.
    Seems to me, that there are some(multiple) factors which
    make H5N1 particularly adapted to 2-3 and that we(nature)
    might have to replace a whole group to achieve the same
    quality of hydrophobic and hydrogen bond interactions
    to 2-6. But also, that if H5N1 could achieve this, then
    it could be much more dangerous for humans. I.e. there
    is some room for "improvement" here. An improvement
    which might not be so easily achieved by random point-mutations
    but rather by a replacement of an entire group
    of amino-acids which are close in the 3d-model
    but not in the 2d-genes. We might look for mutations
    at residue 226 - I think there were none so far.

    Suppose H5N1 would work as good for alphs2-6 as it does for alpha2-3,
    would that mean human pandemic ??
    I'm interested in expert panflu damage estimates
    my current links: http://bit.ly/hFI7H ILI-charts: http://bit.ly/CcRgT

    Comment


    • #3
      Re: Computational studies of H5N1 hemagglutinin binding with SA-α-2, 3-Gal and SA-α-2, 6-

      Suppose H5N1 would work as good for alphs2-6 as it does for alpha2-3,
      would that mean human pandemic ??
      My limited understanding is yes, this is one of the important hurdles the virus needs to accomplish.

      Let me explain what I understand from reading about this, and then please correct me if I have it wrong-I do want to make sure I have it correct!

      Humans have both receptor types- but the A-2,6 are the predominant ones, and found in the upper airway. A virus that binds to that site can enter cells there, and start infection. Since the amount of virus inhaled does remain in the upper airway, a virus with the ability to infect thos esites is more likely to cause illness.

      The human 2,3 sites are in the lower airway, and even if there is an exposure, its less likely the virus will reach the lower airway and cause infection by that route.

      An A-2,6 efficient virus would therefore transmit more easily and efficiently from person to person via casual contact-one of the prerequisites for pandemic spread.

      What I do find fascinating in the article is the reference that the human A-2,6 is a cis- isomer site. My (Again limited) understanding is that most human receptor sites have a cis conformation-which is consistent withhtis information.

      Think nutrition science-one of the dangers of trans-fat ingestion is that when transfats are digested and assimilated into the cell membranes throughout our body, that the receptor sites we need for just about everything to enter the cell become slightly distored, and this negativly affects the free flow of biochemicals into and out of cells.

      The "keys" of chemicals trying to enter a cell via a receptor site dont fit smoothly into the "locks" (the configuaration of the receptor site) in the cells-the shape of the receptor is just a bit different if a transfat has been incorporated into a receptor site molecule.

      I wonder if this is of any importantance when it comes to viral binding. If ingestion of transfats leads to incorporation in htis recetor site, does it create more of a trans configuration? If so, then perhaps susceptability to the avian adapted flu with more alpha 2,3 is increased with higher dietary transfat and incorporation? Do they have more cells that might facitlitate entry?

      What affect might it have on humans if the virus does adapt an a 2,6 preference?
      Upon this gifted age, in its dark hour,
      Rains from the sky a meteoric shower
      Of facts....They lie unquestioned, uncombined.
      Wisdom enough to leech us of our ill
      Is daily spun, but there exists no loom
      To weave it into fabric..
      Edna St. Vincent Millay "Huntsman, What Quarry"
      All my posts to this forum are for fair use and educational purposes only.

      Comment


      • #4
        Re: Computational studies of H5N1 hemagglutinin binding with SA-α-2, 3-Gal and SA-α-2, 6-

        I can't answer this directly but have a few remarks.
        I think, there are also human 2-3 receptors in the upper airway
        but only in some special cells (ciliated or such ?).
        There was an interesting paper earlier this year:
        ----------------------------------------------------------
        Published Online March 16, 2006
        Science DOI: 10.1126/science.1124513
        Science Express Index

        Research Articles
        Submitted on January 3, 2006
        Accepted on February 28, 2006

        Structure and Receptor Specificity of the Hemagglutinin from an H5N1 Influenza Virus
        James Stevens 1*, Ola Blixt 2, Terrence M. Tumpey 3, Jeffery K. Taubenberger 4, James C. Paulson 2, Ian A. Wilson 5*
        1 Department of Molecular Biology
        2 Department of Molecular Biology; Glycan Array Synthesis Core-D, Consortium for Functional Glycomics
        3 Influenza Branch, Division of Viral and Rickettsial Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
        4 Department of Molecular Pathology, Armed Forces Institute of Pathology, Rockville, MD 20306, USA.
        5 Department of Molecular Biology; Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
        ---------------------------------------------------

        and quite some discussion about it in the forums.


        And I remember, that later there was something, that this
        2-3 vs. 2-6 thing was not so decisive and infection
        works also with the wrong receptors...
        (I don't remember exactly)
        Also, quails and pigs(?) have both receptors.

        And it's not only important, where the virus first infects
        the human, but also how good it can subsequently find
        new cells to infect and replicate and spread.


        They should be able to create a recombined H5N1-virus
        with optimal alpha2-6 adapted receptor binding domain
        and test it in ferrets or cats.
        But it could also be that other genes also play a role
        I'm interested in expert panflu damage estimates
        my current links: http://bit.ly/hFI7H ILI-charts: http://bit.ly/CcRgT

        Comment


        • #5
          Re: Computational studies of H5N1 hemagglutinin binding with SA-α-2, 3-Gal and SA-α-2, 6-

          An interesting paper, but possibly not following the argument to its logical conclusion.

          The modelling shows the greater strength ? and number - of the bonds formed between the HA and SA in the a2,3 rather than a2,6 form, given that the HA was from Vietnam in 2004 this is hardly a great surprise, what would be interesting would be to insert some of the documented (or just theoretical) alternative binding sites to see how these change the alignment and bonding strengths. This has the potential to give us advanced notice of HA configurations that should give strong a2,6 binding and we can then watch for mutations which appear to be drifting in a dangerous direction. It would also be interesting to see the same computation with an HA from a a2,6 adapted virus for comparison which should show strong cis and weak trans binding.

          The CDC seems to put a fair bit of weight in the droplet size argument which I have (quite possibly incorrectly) interpreted like this. The lungs have evolved for gas exchange and the vast majority of this occurs in the alveoli (LRT), it would therefore be logical that this, as the main area of tissue/gas interaction, would be the most likely point for a viron to ?land? on the cell surface and this is also where there is a high density of a2,3 SA. Why then does infection not occur here but in the URT ? This may be due to viral load and immune response. A small attack may not be enough to overcome the cells internal non specific immune response, in the URT where larger droplets - containing many virons - precipitate out, the high local load may overwhelm the intracellular defences and begin replication. Once infection is underway the whole respiratory tract is awash with virons and H5N1 seems to have no problem infecting and - with the help of our own immune over reaction ? destroying the (relatively) a2,3 rich LRT.

          As always my ?theories? are aired in the hope someone will correct or refine them and my understanding inch forward.

          Comment


          • #6
            Re: Computational studies of H5N1 hemagglutinin binding with SA-α-2, 3-Gal and SA-α-2, 6-

            And when you get it by eating infected chicken :
            you breathe through the mouth while eating
            and the virus goes into the LRT ?


            earlier threads:

            http://www.flutrackers.com/forum/showthread.php?t=3547

            http://www.flutrackers.com/forum/showthread.php?t=3593
            I'm interested in expert panflu damage estimates
            my current links: http://bit.ly/hFI7H ILI-charts: http://bit.ly/CcRgT

            Comment


            • #7
              Re: Computational studies of H5N1 hemagglutinin binding with SA-α-2, 3-Gal and SA-α-2, 6-

              jjackson, with the droplets you mean normal flu or H5N1 ?
              Normal flu attaches to alph 2-6, not alpha 2-3 AFAIR,
              so it infects the URT where the 2,6 are.
              The droplets are also maybe formed by the humidity in the lungs
              and you get it by breathing out (?)
              Or by mucous in the bronchies.
              With the viral load, I'm not sure since sometimes it seems to work
              even with small load (aerosols). But like you I'm guessing
              I'm interested in expert panflu damage estimates
              my current links: http://bit.ly/hFI7H ILI-charts: http://bit.ly/CcRgT

              Comment


              • #8
                Re: Computational studies of H5N1 hemagglutinin binding with SA-α-2, 3-Gal and SA-α-2, 6-

                Originally posted by LMonty
                I wonder if this is of any importantance when it comes to viral binding. If ingestion of transfats leads to incorporation in htis recetor site, does it create more of a trans configuration? If so, then perhaps susceptability to the avian adapted flu with more alpha 2,3 is increased with higher dietary transfat and incorporation? Do they have more cells that might facitlitate entry?
                No , the glycans on the surface of our cells are a kind of saccharides (sugar) while trans fat are... fat.

                Trans and Cis refer to the way a molecule is twisted around a link and many biologicals molecule can be of the two kind.

                Trans is when the molecule have a arm up and an arm down.
                Cis is when the molecule have both their arm up.
                Do you see the image ?

                I don't beleive there is a link between trans fat and our glycans in the respiratory tract.

                Comment


                • #9
                  Re: Computational studies of H5N1 hemagglutinin binding with SA-α-2, 3-Gal and SA-α-2, 6-

                  All the conformational features derived from computation are consistent with experimental results whenever available and the specific interactions identified are consistent with experimental mutational results. Such general agreement between the computational and experimental results further supports the validity of the important binding features identified in our computational effort.
                  Their model seem to work and would certainly have predicting value.
                  Their extrapolation works may stay unpublished for a while because of the bioterrorist concern.

                  But their way to analyse may be of stong use to develop or to assess the antiviral property of some "easy to produce" peptides that have been tested by others research team...

                  See
                  NOVEL ANTIVIRAL PEPTIDE THAT TARGETS VIRAL ATTACHMENT TO CELLS.
                  From Departments of Medical Microbiology and Immunology and Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI 53706.

                  I think it would be good theses two research team can meet each other and work in the assesment of a potent antiviral peptide that could subsequently be produce by recombinant protein and be grownt on cell culture like yogourt.

                  Comment


                  • #10
                    Re: Computational studies of H5N1 hemagglutinin binding with SA-α-2, 3-Gal and SA-α-2, 6-

                    But the data exposed there point out in the direction on G226 wich have the strongest sets on interaction and is precicely the one that a2,6cis can't bind with.

                    Comment


                    • #11
                      Re: Computational studies of H5N1 hemagglutinin binding with SA-α-2, 3-Gal and SA-α-2, 6-

                      There have been a cluster with a Q226R mutation in january of this year
                      A/Indonesia/CDC329/2006

                      Comment


                      • #12
                        Re: Computational studies of H5N1 hemagglutinin binding with SA-α-2, 3-Gal and SA-α-2, 6-

                        gsgs

                        I think the droplets the CDC were referring to were the larger ones that settle out relatively quickly created by sneezing. Obviously there are going to be a wide range of droplets sizes from very fine to lumps. I suspect it is all down to probabilities/luck, sometimes one viron can cause illness and on other occasions not, but the higher the load in the initial challenge the greater the chance of it resulting in clinical illness. In LP seasonal flu infection seems to occur via the clara epithelial cells in the URT but this is not just due to them having a2,6 SA but more to do with the local clara protease being capable of cleaving the HA. The polybasic cleavage domain of HP H5N1 removes this impediment as a wide range of common proteases can cleave it (see thread in Mingus? Lab). In the case of infection by ingestion I assumed that the food was inadequately cooked and the virus found some other cell in the alimentary tract to enter through, unless infection occurred during preparation or contamination of the preparation area. As I understand it a2,3 & a2,6 sugars can be found in quite a few areas of the body and both are found in both URT & LRT but that a2,3 are more common in the LRT (and eyes) and a2,6 in the URT.

                        Comment


                        • #13
                          Re: Computational studies of H5N1 hemagglutinin binding with SA-α-2, 3-Gal and SA-α-2, 6-

                          I could not edit my last post to add the link to the Mingus' Lab thread http://www.flutrackers.com/forum/sho...?t=3901&page=2 but on rereading parts of t I find all the contributors to this thread also posted in that one.

                          Comment


                          • #14
                            Re: Computational studies of H5N1 hemagglutinin binding with SA-α-2, 3-Gal and SA-α-2, 6-

                            Thanks for the feedback guys- I aoppreicat eit. I had a fundamental error in understanding- I though the receptor site molecules were composed of molecules that included sugars and lipids. Did a quick check, and its glycoproteins! my error, thanks for the info.

                            I really, really need to read more abut this and understand it better! The biochemistry class is helping a bit, but its coming at me so fast, I am starting to scramble things up.
                            Upon this gifted age, in its dark hour,
                            Rains from the sky a meteoric shower
                            Of facts....They lie unquestioned, uncombined.
                            Wisdom enough to leech us of our ill
                            Is daily spun, but there exists no loom
                            To weave it into fabric..
                            Edna St. Vincent Millay "Huntsman, What Quarry"
                            All my posts to this forum are for fair use and educational purposes only.

                            Comment


                            • #15
                              Re: Computational studies of H5N1 hemagglutinin binding with SA-α-2, 3-Gal and SA-α-2, 6-

                              Originally posted by JJackson
                              I could not edit my last post to add the link to the Mingus' Lab thread http://www.flutrackers.com/forum/sho...?t=3901&page=2 but on rereading parts of t I find all the contributors to this thread also posted in that one.

                              yes, that looks very informative and important but also
                              very long and hard to read. If I ever understood this well,
                              then I'd forgotten.
                              So, if someone could give a summary or conclusion chapter,
                              that would be useful.


                              I also just read this on another board: (JKT=Taubenberger)

                              significance of receptor binding: In this paper that JKT co-authored Glycan Microarray Analysis of the Hemagglutinins from Modern and Pandemic Influenza Viruses Reveals Different Receptor Specificities, Stevens et al they measured the receptor binding affinity of 2 different strains of the 1918 virus, one from South Carolina (18SC) and one from New York (18NY). What they found was that 18NY had one mutation from 18SC. Whereas 18SC showed strong affinity to alpha2,6 (human) and no affinity for alpha2,3 (avian) receptors, 18NY showed significant reduction in binding to alpha2,6 and a gain in affinity to alpha2,3 receptors. And yet, there was no difference in clinical presentation, pathogenesis, mortality, transmissibility between the 2 strains. What does this mean? It could be that receptor binding is only important in an on/off fashion, and not as a matter of degree. That is, as long as there is some affinity, it is sufficient for the virus to do the rest of the job, and the degree of affinity does not affect the outcome at all.
                              I'm interested in expert panflu damage estimates
                              my current links: http://bit.ly/hFI7H ILI-charts: http://bit.ly/CcRgT

                              Comment

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