School of Physics, Georgia Institute of Technology, Atlanta, Georgia 30332, United States.
UT/ORNL Center for Molecular Biophysics, Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States.
J Phys Chem Lett. 2021 Jun 17;12(23):5494-5502. doi: 10.1021/acs.jpclett.1c01494. Epub 2021 Jun 4.
SARS-CoV and SARS-CoV-2 bind to the human ACE2 receptor in practically identical conformations, although several residues of the receptor-binding domain (RBD) differ between them. Herein, we have used molecular dynamics (MD) simulations, machine learning (ML), and free-energy perturbation (FEP) calculations to elucidate the differences in binding by the two viruses. Although only subtle differences were observed from the initial MD simulations of the two RBD-ACE2 complexes, ML identified the individual residues with the most distinctive ACE2 interactions, many of which have been highlighted in previous experimental studies. FEP calculations quantified the corresponding differences in binding free energies to ACE2, and examination of MD trajectories provided structural explanations for these differences. Lastly, the energetics of emerging SARS-CoV-2 mutations were studied, showing that the affinity of the RBD for ACE2 is increased by N501Y and E484K mutations but is slightly decreased by K417N.
SARS-CoV 和 SARS-CoV-2 以几乎相同的构象结合到人类 ACE2 受体上，尽管受体结合域（RBD）的几个残基在它们之间存在差异。在此，我们使用分子动力学（MD）模拟、机器学习（ML）和自由能微扰（FEP）计算来阐明两种病毒的结合差异。尽管从最初的 RBD-ACE2 复合物的 MD 模拟中仅观察到细微差异，但 ML 确定了与 ACE2 具有最独特相互作用的单个残基，其中许多残基已在先前的实验研究中得到强调。FEP 计算量化了与 ACE2 结合自由能的相应差异，对 MD 轨迹的检查为这些差异提供了结构解释。最后，研究了 SARS-CoV-2 新兴突变的能量学，表明 RBD 对 ACE2 的亲和力通过 N501Y 和 E484K 突变而增加，但通过 K417N 突变略有降低。
