由SARS-CoV-2引起的COVID-19已在世界各地传播。SARS-CoV-2刺突蛋白的受体结合域(RBD)是与宿主ACE2直接相互作用的关键成分。这里,我们模拟了WT的RBD的ACE2识别过程,Delta,和OmicronBA.2变体使用我们最近开发的监督高斯加速分子动力学(Su-GaMD)方法。我们证明RBD通过三个接触区域(区域I,II,andIII),它与锚锁机构很好地对齐。与其他变体相比,RBDOmicronBA.2-ACE2系统在状态d中较高的结合自由能与OmicronBA.2的感染性增加密切相关。对于RBDDelta,T478K突变影响识别的第一步,而L452R突变,通过其附近的Y449,在识别的最后一步中影响RBDDelta-ACE2结合。对于RBDOmicronBA.2,E484A突变影响识别的第一步,Q493R,N501Y,Y505H突变影响识别最后一步的结合自由能,接触区域的突变直接影响识别,和其他突变通过与接触区域的动态相关性间接影响识别。这些结果为RBD-ACE2识别提供了理论见解,并可能促进针对SARS-CoV-2的药物设计。
COVID-19 caused by SARS-CoV-2 has spread around the world. The receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 is a critical component that directly interacts with host ACE2. Here, we simulate the ACE2 recognition processes of RBD of the WT, Delta, and OmicronBA.2 variants using our recently developed supervised Gaussian accelerated molecular dynamics (Su-GaMD) approach. We show that RBD recognizes ACE2 through three contact regions (regions I, II, and III), which aligns well with the anchor-locker mechanism. The higher binding free energy in State d of the RBDOmicronBA.2-ACE2 system correlates well with the increased infectivity of OmicronBA.2 in comparison with other variants. For RBDDelta, the T478K mutation affects the first step of recognition, while the L452R mutation, through its nearby Y449, affects the RBDDelta-ACE2 binding in the last step of recognition. For RBDOmicronBA.2, the E484A mutation affects the first step of recognition, the Q493R, N501Y, and Y505H mutations affect the binding free energy in the last step of recognition, mutations in the contact regions affect the recognition directly, and other mutations indirectly affect recognition through dynamic correlations with the contact regions. These results provide theoretical insights for RBD-ACE2 recognition and may facilitate drug design against SARS-CoV-2.