Taka Elhan, Yilmaz Sema Z, Golcuk Mert, Kilinc Ceren, Aktas Umut, Yildiz Ahmet, Gur Mert
Department of Mechanical Engineering, Istanbul Technical University (ITU), 34437 Istanbul, Turkey.
Physics Department, University of California, Berkeley, California 94720-3220, United States.
J Phys Chem B. 2021 Jun 3;125(21):5537-5548. doi: 10.1021/acs.jpcb.1c02048. Epub 2021 May 12.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects human cells by binding its spike (S) glycoproteins to angiotensin-converting enzyme 2 (ACE2) receptors and causes the coronavirus disease 2019 (COVID-19). Therapeutic approaches to prevent SARS-CoV-2 infection are mostly focused on blocking S-ACE2 binding, but critical residues that stabilize this interaction are not well understood. By performing all-atom molecular dynamics (MD) simulations, we identified an extended network of salt bridges, hydrophobic and electrostatic interactions, and hydrogen bonds between the receptor-binding domain (RBD) of the S protein and ACE2. Mutagenesis of these residues on the RBD was not sufficient to destabilize binding but reduced the average work to unbind the S protein from ACE2. In particular, the hydrophobic end of RBD serves as the main anchor site and is the last to unbind from ACE2 under force. We propose that blocking the hydrophobic surface of RBD via neutralizing antibodies could prove to be an effective strategy to inhibit S-ACE2 interactions.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）通过其刺突（S）糖蛋白与血管紧张素转换酶2（ACE2）受体结合来感染人类细胞，并引发2019冠状病毒病（COVID-19）。预防SARS-CoV-2感染的治疗方法大多集中在阻断S-ACE2结合，但稳定这种相互作用的关键残基尚未得到充分了解。通过进行全原子分子动力学（MD）模拟，我们确定了S蛋白的受体结合域（RBD）与ACE2之间存在一个由盐桥、疏水和静电相互作用以及氢键组成的扩展网络。对RBD上这些残基进行诱变不足以破坏结合，但降低了将S蛋白从ACE2上解离的平均功。特别是，RBD的疏水末端作为主要的锚定位点，在受力情况下是最后一个从ACE2上解离的。我们提出，通过中和抗体阻断RBD的疏水表面可能是抑制S-ACE2相互作用的有效策略。
