The spread of the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has become a global health crisis. The binding affinity of SARS-CoV-2 (in particular the receptor binding domain, RBD) to its receptor angiotensin converting enzyme 2 (ACE2) and the antibodies is of great importance in understanding the infectivity of COVID-19 and evaluating the candidate therapeutic for COVID-19. We propose a new method based on molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA) to accurately calculate the free energy of SARS-CoV-2 RBD binding to ACE2 and antibodies. The calculated binding free energy of SARS-CoV-2 RBD to ACE2 is –13.3 kcal/mol, and that of SARS-CoV RBD to ACE2 is –11.4 kcal/mol, which agree well with the experimental results of –11.3 kcal/mol and –10.1 kcal/mol, respectively. Moreover, we take two recently reported antibodies as examples, and calculate the free energy of antibodies binding to SARS-CoV-2 RBD, which is also consistent with the experimental findings. Further, within the framework of the modified MM/PBSA, we determine the key residues and the main driving forces for the SARS-CoV-2 RBD/CB6 interaction by the computational alanine scanning method. The present study offers a computationally efficient and numerically reliable method to evaluate the free energy of SARS-CoV-2 binding to other proteins, which may stimulate the development of the therapeutics against the COVID-19 disease in real applications.

由严重急性呼吸系统综合症冠状病毒2（SARS-CoV-2）引起的冠状病毒疾病2019（COVID-19）的传播已成为全球健康危机。SARS-CoV-2（特别是受体结合结构域RBD）与其受体血管紧张素转换酶2（ACE2）和抗体的结合亲和力对于理解COVID-19的感染性和评估候选治疗药物具有重要意义。新型冠状病毒肺炎（COVID-19）：新冠肺炎（COVID-19）：COVID-19。我们提出一种基于分子力学/泊松-玻尔兹曼表面积（MM / PBSA）的新方法，以准确计算SARS-CoV-2 RBD与ACE2和抗体结合的自由能。SARS-CoV-2 RBD与ACE2的结合自由能为–13.3 kcal / mol，SARS-CoV RBD与ACE2的结合自由能为–11.4 kcal / mol，与–11.3 kcal / mol的实验结果吻合得很好。和–10.1 kcal / mol。此外，我们以两种最近报道的抗体为例，并计算了与SARS-CoV-2 RBD结合的抗体的自由能，这也与实验结果一致。此外，在改进的MM / PBSA框架内，我们通过计算丙氨酸扫描方法确定了SARS-CoV-2 RBD / CB6相互作用的关键残基和主要驱动力。本研究提供了一种计算有效且在数值上可靠的方法来评估SARS-CoV-2与其他蛋白质结合的自由能，这可能会刺激在实际应用中对抗COVID-19疾病的疗法的发展。在改进的MM / PBSA框架内，我们通过计算丙氨酸扫描法确定了SARS-CoV-2 RBD / CB6相互作用的关键残基和主要驱动力。本研究提供了一种计算有效且在数值上可靠的方法来评估SARS-CoV-2与其他蛋白质结合的自由能，这可能会刺激在实际应用中对抗COVID-19疾病的疗法的发展。在改进的MM / PBSA框架内，我们通过计算丙氨酸扫描法确定了SARS-CoV-2 RBD / CB6相互作用的关键残基和主要驱动力。本研究提供了一种计算有效且在数值上可靠的方法来评估SARS-CoV-2与其他蛋白质结合的自由能，这可能会刺激在实际应用中对抗COVID-19疾病的疗法的发展。