Socher Eileen, Conrad Marcus, Heger Lukas, Paulsen Friedrich, Sticht Heinrich, Zunke Friederike, Arnold Philipp
Institute of Anatomy, Functional and Clinical Anatomy, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany.
Institute for Clinical and Molecular Virology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital Erlangen, 91054 Erlangen, Germany.
Biomedicines. 2021 May 8;9(5):525. doi: 10.3390/biomedicines9050525.
The B.1.1.7 variant of the SARS-CoV-2 virus shows enhanced infectiousness over the wild type virus, leading to increasing patient numbers in affected areas. Amino acid exchanges within the SARS-CoV-2 spike protein variant of B.1.1.7 affect inter-monomeric contact sites within the trimer (A570D and D614G) as well as the ACE2-receptor interface region (N501Y), which comprises the receptor-binding domain (RBD) of the spike protein. However, the molecular consequences of mutations within B.1.1.7 on spike protein dynamics and stability or ACE2 binding are largely unknown. Here, molecular dynamics simulations comparing SARS-CoV-2 wild type with the B.1.1.7 variant revealed inter-trimeric contact rearrangements, altering the structural flexibility within the spike protein trimer. Furthermore, we found increased flexibility in direct spatial proximity of the fusion peptide due to salt bridge rearrangements induced by the D614G mutation in B.1.1.7. This study also implies a reduced binding affinity for B.1.1.7 with ACE2, as the N501Y mutation restructures the RBD-ACE2 interface, significantly decreasing the linear interaction energy between the RBD and ACE2. Our results demonstrate how mutations found within B.1.1.7 enlarge the flexibility around the fusion peptide and change the RBD-ACE2 interface. We anticipate our findings to be starting points for in depth biochemical and cell biological analyses of B.1.1.7.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的B.1.1.7变体比野生型病毒表现出更强的传染性，导致受影响地区的患者数量不断增加。B.1.1.7的SARS-CoV-2刺突蛋白变体中的氨基酸交换影响三聚体中的单体间接触位点（A570D和D614G）以及血管紧张素转换酶2（ACE2）受体界面区域（N501Y），该区域包含刺突蛋白的受体结合域（RBD）。然而，B.1.1.7内突变对刺突蛋白动力学、稳定性或ACE2结合的分子后果在很大程度上尚不清楚。在这里，将SARS-CoV-2野生型与B.1.1.7变体进行比较的分子动力学模拟揭示了三聚体间接触的重新排列，改变了刺突蛋白三聚体内的结构灵活性。此外，我们发现由于B.1.1.7中D614G突变引起的盐桥重排，融合肽直接空间邻近区域的灵活性增加。这项研究还表明B.1.1.7与ACE2的结合亲和力降低，因为N501Y突变重构了RBD-ACE2界面，显著降低了RBD与ACE2之间的线性相互作用能。我们的结果证明了B.1.1.7中发现的突变如何扩大融合肽周围的灵活性并改变RBD-ACE2界面。我们预计我们的发现将成为对B.1.1.7进行深入生化和细胞生物学分析的起点。
