Mutations in the B.1.1.7 SARS-CoV-2 Spike Protein Reduce Receptor-Binding Affinity and Induce a Flexible Link to the Fusion Peptide.
Mutations in the B.1.1.7 SARS-CoV-2 Spike Protein Reduce Receptor-Binding Affinity and Induce a Flexible Link to the Fusion Peptide.
复制标题
B.1.1.7 SARS-CoV-2刺突蛋白的突变降低了受体结合亲和力，并诱导了与融合肽的灵活链接。
DOI：
10.3390/biomedicines9050525
复制
发表时间：
2021-05-08
期刊：
影响因子：
4.7
通讯作者：
Arnold P
中科院分区：
文献类型：
--
作者：
Socher E;Conrad M;Heger L;Paulsen F;Sticht H;Zunke F;Arnold P
SARS-CoV-2病毒的B.1.1.7变体显示出比野生型病毒更强的感染性，导致受影响地区的患者人数增加。B.1.1.7的SARS-CoV-2刺突蛋白变体内的氨基酸交换影响三聚体内的单体间接触位点（A570 D和D 614 G）以及ACE 2-受体界面区（N501 Y），其包含刺突蛋白的受体结合结构域（RBD）。然而，B.1.1.7内突变对刺突蛋白动力学和稳定性或ACE 2结合的分子后果在很大程度上是未知的。在这里，比较SARS-CoV-2野生型与B.1.1.7变体的分子动力学模拟揭示了三聚体间的接触重排，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中的D 614 G突变诱导的盐桥重排，融合肽的直接空间接近性增加了灵活性。该研究还表明B.1.1.7与ACE 2的结合亲和力降低，因为N501 Y突变重构了RBD-ACE 2界面，显著降低了RBD和ACE 2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-ACE 2界面。我们希望我们的发现是深入的生化和细胞生物学分析B.1.1.7的起点。
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.
登录
查看更多内容
影响因子：
64.8
作者：
Plante JA;Liu Y;Liu J;Xia H;Johnson BA;Lokugamage KG;Zhang X;Muruato AE;Zou J;Fontes-Garfias CR;Mirchandani D;Scharton D;Bilello JP;Ku Z;An Z;Kalveram B;Freiberg AN;Menachery VD;Xie X;Plante KS;Weaver SC;Shi PY
通讯作者：
Shi PY
DOI：
10.1126/science.abe8499
发表时间：
2020-12-18
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hou YJ;Chiba S;Halfmann P;Ehre C;Kuroda M;Dinnon KH 3rd;Leist SR;Schäfer A;Nakajima N;Takahashi K;Lee RE;Mascenik TM;Graham R;Edwards CE;Tse LV;Okuda K;Markmann AJ;Bartelt L;de Silva A;Margolis DM;Boucher RC;Randell SH;Suzuki T;Gralinski LE;Kawaoka Y;Baric RS
通讯作者：
Baric RS
影响因子：
5.5
作者：
Goetz, Andreas W.;Williamson, Mark J.;Xu, Dong;Poole, Duncan;Le Grand, Scott;Walker, Ross C.
通讯作者：
Walker, Ross C.
影响因子：
5.5
作者：
Roe, Daniel R.;Cheatham, Thomas E., III
通讯作者：
Cheatham, Thomas E., III
影响因子：
5.5
作者：
Salomon-Ferrer, Romelia;Goetz, Andreas W.;Walker, Ross C.
通讯作者：
Walker, Ross C.