Tang Can, Lupala Cecylia S, Wang Ding, Li Xiangcheng, Tang Lei-Han, Li Xuefei
State Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
Int J Mol Sci. 2025 Apr 17;26(8):3776. doi: 10.3390/ijms26083776.
The evolution of SARS-CoV-2, particularly the emergence of Omicron variants, has raised questions regarding changes in its binding affinity to the human angiotensin-converting enzyme 2 receptor (hACE2). Understanding the impact of mutations on the interaction between the receptor-binding domain (RBD) of the spike protein and hACE2 is critical for evaluating viral transmissibility, immune evasion, and the efficacy of therapeutic strategies. Here, we used molecular dynamics (MD) simulations and binding energy calculations to investigate the structural and energetic differences between the hACE2- RBD complexes of wild-type (WT), Delta, and Omicron subvariants. Our results indicate that the Delta and the first Omicron variants showed the highest and the second-highest binding energy among the variants studied. Furthermore, while Omicron variants exhibit increased structural stability and altered electrostatic potential at the hACE2-RBD interface when compared to the ancestral WT, their binding strength to hACE2 does not consistently increase with viral evolution. Moreover, newer Omicron subvariants like JN.1 exhibit a bimodal conformational strategy, alternating between a high-affinity state for hACE2 and a low-affinity state, which could potentially facilitate immune evasion. These findings suggest that, in addition to enhanced hACE2 binding affinity, other factors, such as immune evasion and structural adaptability, shape SARS-CoV-2 evolution.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的进化，尤其是奥密克戎变种的出现，引发了关于其与人血管紧张素转换酶2受体（hACE2）结合亲和力变化的问题。了解突变对刺突蛋白受体结合域（RBD）与hACE2之间相互作用的影响，对于评估病毒传播性、免疫逃逸及治疗策略的疗效至关重要。在此，我们使用分子动力学（MD）模拟和结合能计算，来研究野生型（WT）、德尔塔和奥密克戎亚变种的hACE2-RBD复合物之间的结构和能量差异。我们的结果表明，在所研究的变种中，德尔塔变种和首个奥密克戎变种的结合能分别最高和第二高。此外，与原始野生型相比，奥密克戎变种在hACE2-RBD界面处表现出更高的结构稳定性和改变的静电势，但其与hACE2的结合强度并未随病毒进化而持续增加。此外，像JN.1这样较新的奥密克戎亚变种呈现出一种双峰构象策略，在对hACE2的高亲和力状态和低亲和力状态之间交替，这可能有助于免疫逃逸。这些发现表明，除了增强的hACE2结合亲和力外，其他因素，如免疫逃逸和结构适应性，也塑造了SARS-CoV-2的进化。
