Enhanced receptor binding of SARS-CoV-2 through networks of hydrogen-bonding and interactions
Enhanced receptor binding of SARS-CoV-2 through networks of hydrogen-bonding and interactions
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通过氢键和疏水相互作用网络增强 SARS-CoV-2 的受体结合
DOI：
10.1073/pnas.2008209117
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发表时间：
2020-06-23
影响因子：
11.1
通讯作者：
Gao, Jiali
中科院分区：
文献类型：
--
作者：
Wang, Yingjie;Liu, Meiyi;Gao, Jiali
进行了分子动力学和自由能模拟，以阐明普通受体蛋白血管紧张素转换酶2（ACE2）与严重急性呼吸综合征冠状病毒2（SARS - CoV - 2）[A. E. Gorbalenya等人，《自然微生物学》5，536 - 544（2020）]的受体结合域之间不同的蛋白质 - 蛋白质相互作用的结构起源，SARS - CoV - 2导致了2019冠状病毒病（COVID - 19）[P. Zhou等人，《自然》579，270 - 273（2020）]，以及2002 - 2003年（SARS - CoV）[T. Kuiken等人，《柳叶刀》362，263 - 270（2003）]爆发的SARS冠状病毒。对动态轨迹的分析表明，在2019新型冠状病毒中，结合界面由一个主要的疏水区域和一个精细的氢键网络组成。SARS - CoV序列中一个疏水残基到SARS - CoV - 2中Lys417的关键突变在中央疏水接触区域形成了一个盐桥，再加上极性残基突变，导致其静电互补性比SARS - CoV复合物更强。此外，与SARS - CoV复合物相比，由于在一个短的12个残基的环中去除了五个脯氨酸残基中的四个，静电效应和增强的疏水堆积都导致复合物向一个更倾斜的结合凹槽发生构象转变。另一方面，在SARS - CoV中和抗体80R的复合物中的疏水接触在SARS - CoV - 2同源复合物模型中被破坏，这归因于80R无法识别SARS - CoV - 2。
Significance Enhanced receptor binding by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is believed to contribute to the highly contagious transmission rate of coronavirus disease 2019. An understanding of the structural and energetic details responsible for protein–protein interactions between the host receptor ACE2 and SARS-CoV-2 can be useful to epidemic surveillance, diagnosis, and optimization of neutralizing agents. The present study unravels a delicate balance of specific and nonspecific hydrogen-bonding and hydrophobic networks to help elucidate the similarities and differences in receptor binding by SARS-CoV-2 and SARS-CoV. Molecular dynamics and free energy simulations have been carried out to elucidate the structural origin of differential protein–protein interactions between the common receptor protein angiotensin converting enzyme 2 (ACE2) and the receptor binding domains of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [A. E. Gorbalenya et al., Nat. Microbiol. 5, 536–544 (2020)] that causes coronavirus disease 2019 (COVID-19) [P. Zhou et al., Nature 579, 270–273 (2020)] and the SARS coronavirus in the 2002–2003 (SARS-CoV) [T. Kuiken et al., Lancet 362, 263–270 (2003)] outbreak. Analysis of the dynamic trajectories reveals that the binding interface consists of a primarily hydrophobic region and a delicate hydrogen-bonding network in the 2019 novel coronavirus. A key mutation from a hydrophobic residue in the SARS-CoV sequence to Lys417 in SARS-CoV-2 creates a salt bridge across the central hydrophobic contact region, which along with polar residue mutations results in greater electrostatic complementarity than that of the SARS-CoV complex. Furthermore, both electrostatic effects and enhanced hydrophobic packing due to removal of four out of five proline residues in a short 12-residue loop lead to conformation shift toward a more tilted binding groove in the complex in comparison with the SARS-CoV complex. On the other hand, hydrophobic contacts in the complex of the SARS-CoV–neutralizing antibody 80R are disrupted in the SARS-CoV-2 homology complex model, which is attributed to failure of recognition of SARS-CoV-2 by 80R.