Peng Cheng, Zhu Zhengdan, Shi Yulong, Wang Xiaoyu, Mu Kaijie, Yang Yanqing, Zhang Xinben, Xu Zhijian, Zhu Weiliang
CAS Key Laboratory of Receptor Research; Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
J Phys Chem Lett. 2020 Dec 17;11(24):10482-10488. doi: 10.1021/acs.jpclett.0c02958. Epub 2020 Dec 4.
The spike protein of SARS-CoV-2 (CoV-2-S) mediates the virus entry into human cells. Experimental studies have shown the stronger binding affinity of the RBD (receptor binding domain) of CoV-2-S to angiotensin-converting enzyme 2 (ACE2) as compared to that of SARS-CoV spike (CoV-S). However, a similar or weaker binding affinity of CoV-2-S compared to that of CoV-S is observed if entire spikes are used in the bioassay. To explore the underlying mechanism, we calculated the binding affinities of the RBDs to ACE2 and simulated the transitions between ACE2-inaccessible and -accessible conformations. We found that the ACE2-accessible angle of CoV-2-S is 52.2° and that the ACE2 binding strength of CoV-2-S RBD is much stronger than that of CoV-S RBD. However, CoV-2-S has much less of an ACE2-accessible conformation and is much more difficult to shift from ACE2-inaccessible to -accessible than CoV-S, making the binding affinity of the entire protein decrease. Further analysis revealed key interactional residues for strong binding and five potential ligand-binding pockets for drug research.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的刺突蛋白（CoV-2-S）介导病毒进入人体细胞。实验研究表明，与SARS-CoV刺突（CoV-S）相比，CoV-2-S的受体结合域（RBD）与血管紧张素转换酶2（ACE2）的结合亲和力更强。然而，如果在生物测定中使用完整的刺突，则观察到CoV-2-S与CoV-S相比具有相似或较弱的结合亲和力。为了探究其潜在机制，我们计算了RBD与ACE2的结合亲和力，并模拟了ACE2不可接近和可接近构象之间的转变。我们发现CoV-2-S的ACE2可接近角度为52.2°，并且CoV-2-S RBD的ACE2结合强度比CoV-S RBD强得多。然而，CoV-2-S具有ACE2可接近构象的比例要少得多，并且比CoV-S更难从ACE2不可接近构象转变为可接近构象，这使得整个蛋白质的结合亲和力降低。进一步分析揭示了强结合的关键相互作用残基以及用于药物研究的五个潜在配体结合口袋。
