a Faculty of Science, Department of Chemistry, Center of Excellence in Computational Chemistry (CECC) , Chulalongkorn University , Bangkok , Thailand.
b Faculty of Science, Department of Biochemistry, Structural and Computational Biology Research Group , Chulalongkorn University , Bangkok , Thailand.
J Biomol Struct Dyn. 2019 Aug;37(13):3354-3365. doi: 10.1080/07391102.2018.1514326. Epub 2018 Nov 25.
Two important glycoproteins on the influenza virus membrane, hemagglutinin (HA) and neuraminidase (NA), are relevant to virus replication. As previously reported, HA has a substrate specificity towards SIA-2,3-GAL-1,4-NAG (3SL) and SIA-2,6-GAL-1,4-NAG (6SL) glycans, while NA can cleave both types of linkages. However, the substrate binding into NA and its preference are not well understood. In this work, the glycan binding and specificity of human and avian NAs were evaluated by classical molecular dynamics (MD) simulations, whilst the conformational diversity of 3SL avian and 6SL human glycans in an unbound state was investigated by replica exchange MD simulations. The results indicated that the 3SL avian receptor fits well in the binding cavity of all NAs and does not require a conformational change for such binding compared to the flexible shape of the 6SL human receptor. From the QM/MM-GBSA binding free energy and decomposition free energy data, 6SL showed a much stronger binding towards human NAs (H1N1, H2N2 and H3N2) than to avian NAs (H5N1 and H7N9). This suggests that influenza NAs have a substrate specificity corresponding to their HA, indicating the functional balance between the two important glycoproteins. Both linkages show distinct glycan topologies when complexed with NAs, while the flexibility of torsion angles between GAL and NAG in 6SL results in the various shapes of glycan and different binding patterns. Lower conformational diversities of both glycans when bound to NA compared to the unbound state were found, and were required in order to be accommodated within the NA cavity. Communicated by Ramaswamy H. Sarma.
流感病毒膜上的两种重要糖蛋白，血凝素 (HA) 和神经氨酸酶 (NA)，与病毒复制有关。如前所述，HA 对 SIA-2,3-GAL-1,4-NAG（3SL）和 SIA-2,6-GAL-1,4-NAG（6SL）糖具有底物特异性，而 NA 可以裂解这两种键。然而，NA 的底物结合及其偏好性尚不清楚。在这项工作中，通过经典分子动力学 (MD) 模拟评估了人和禽流感病毒 NA 的糖结合和特异性，而通过 replica exchange MD 模拟研究了未结合状态下 3SL 禽和 6SL 人糖的构象多样性。结果表明，3SL 禽受体与所有 NA 的结合腔非常吻合，与灵活的 6SL 人受体形状相比，不需要构象变化即可进行这种结合。从 QM/MM-GBSA 结合自由能和分解自由能数据来看，6SL 与人 NAs（H1N1、H2N2 和 H3N2）的结合比与禽 NAs（H5N1 和 H7N9）强得多。这表明流感病毒 NA 具有与其 HA 相对应的底物特异性，表明两种重要糖蛋白之间存在功能平衡。两种键与 NA 结合时都显示出不同的糖拓扑结构，而 6SL 中 GAL 和 NAG 之间的扭转角灵活性导致了糖的各种形状和不同的结合模式。与未结合状态相比，当与 NA 结合时，两种糖的构象多样性都较低，并且需要在 NA 腔中容纳。由 Ramaswamy H. Sarma 传达。
