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

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    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].

    http://www.sciencedirect.com/cache/M...=dGLbVtz-zSkWW
    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%">
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    http://www.sciencedirect.com/cache/M...=dGLbVtz-zSkWA
    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%">
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    http://www.sciencedirect.com/cache/M...=dGLbVtz-zSkzV
    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>
    http://www.sciencedirect.com/cache/M...=dGLbVzb-zSkzV
    Fig. 4. A schematic illustration of the interactions of SA-α-2, 6-Gal with residues around the receptor site of H5N1 hemagglutinin.

    http://www.sciencedirect.com/cache/M...=dGLbVtz-zSkzS
    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.


    http://www.sciencedirect.com/cache/M...=dGLbVtb-zSkzS
    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%">
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    http://www.sciencedirect.com/cache/M...=dGLzVzz-zSkzk
    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.



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    </td> </tr> </tbody></table> <!-- / user info --> </td> </tr> <tr> <td class="alt1" id="td_post_36131"> <!-- message, attachments, sig --> <!-- icon and title --> Re: Computational studies of H5N1 hemagglutinin binding with SA-α-2, 3-Gal and SA-α-2, 6-
    <hr style="color: rgb(204, 204, 204);" size="1"> <!-- / icon and title --> <!-- message --> 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 ??
    <!-- / message -->
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