Cheminformatics Research Unit, Department of Chemistry, Faculty of Science, Kasetsart University, Thailand.
BMC Genomics. 2009 Dec 3;10 Suppl 3(Suppl 3):S24. doi: 10.1186/1471-2164-10-S3-S24.
It is known that the highly pathogenic avian influenza A virus H5N1 binds strongly and with high specificity to the avian-type receptor by its hemagglutinin surface protein. This specificity is normally a barrier to viral transmission from birds to humans. However, strains may emerge with mutated hemagglutinin, potentially changing the receptor binding preference from avian to human-type. This hypothesis has been proven correct, since viral isolates from Vietnam and Thailand have been found which have increased selectivity toward the human cell receptor. The change in binding preference is due to mutation, which can be computationally modelled. The aim of this study is to further explore whether computational simulation could be used as a prediction tool for host type selectivity in emerging variants.
Molecular dynamics simulation was employed to study the interactions between receptor models and hemagglutinin proteins from H5N1 strains A/Duck/Singapore/3/97, mutated A/Duck/Singapore/3/97 (Q222L, G224S, Q222L/G224S), A/Thailand/1(KAN-1)/2004, and mutated A/Thailand/1(KAN-1)/2004 (L129V/A134V). The avian receptor was represented by Sia alpha(2,3)Gal substructure and human receptor by Sia alpha(2,6)Gal. The glycoside binding conformation was monitored throughout the simulations since high selectivity toward a particular host occurs when the sialoside bound with the near-optimized conformation.
The simulation results showed all hemagglutinin proteins used the same set of amino acid residues to bind with the glycoside; however, some mutations alter linkage preferences. Preference toward human-type receptors is associated with a positive torsion angle, while avian-type receptor preference is associated with a negative torsion angle. According to the conformation analysis of the bound receptors, we could predict the relative selectivity in accordance with in vitro experimental data when disaccharides receptor analogs were used.
众所周知，高致病性禽流感病毒 H5N1 通过其血凝素表面蛋白强烈且特异性地结合禽型受体。这种特异性通常是病毒从鸟类传播到人类的障碍。然而，可能会出现具有突变血凝素的菌株，从而潜在改变对人类型受体的结合偏好。这一假设已被证明是正确的，因为已经发现来自越南和泰国的病毒分离株对人类细胞受体具有更高的选择性。结合偏好的改变归因于突变，而突变可以通过计算模型进行模拟。本研究的目的是进一步探索计算模拟是否可作为预测宿主类型选择性的新兴变体的工具。
采用分子动力学模拟研究了 H5N1 株 A/Duck/Singapore/3/97、突变株 A/Duck/Singapore/3/97（Q222L、G224S、Q222L/G224S）、A/Thailand/1(KAN-1)/2004 和突变株 A/Thailand/1(KAN-1)/2004（L129V/A134V）的血凝素蛋白与受体模型之间的相互作用。禽型受体由 Sia alpha(2,3)Gal 亚结构表示，而人型受体由 Sia alpha(2,6)Gal 表示。由于当唾液酸结合具有近优化构象时，对特定宿主具有高选择性，因此在整个模拟过程中监测糖苷结合构象。
模拟结果表明，所有血凝素蛋白都使用相同的氨基酸残基集与糖苷结合；然而，一些突变改变了键合偏好。对人型受体的偏好与正扭转角相关，而对禽型受体的偏好与负扭转角相关。根据结合受体的构象分析，当使用二糖受体类似物时，我们可以根据体外实验数据预测相对选择性。
