Department of Physics, School of Science, Tianjin University, Tianjin 300072, China.
Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin 300072, China.
Brief Bioinform. 2021 Mar 22;22(2):1122-1136. doi: 10.1093/bib/bbab044.
Temperature plays a significant role in the survival and transmission of SARS-CoV (severe acute respiratory syndrome coronavirus) and SARS-CoV-2. To reveal the binding differences of SARS-CoV and SARS-CoV-2 receptor-binding domains (RBDs) to angiotensin-converting enzyme 2 (ACE2) at different temperatures at atomic level, 20 molecular dynamics simulations were carried out for SARS-CoV and SARS-CoV-2 RBD-ACE2 complexes at five selected temperatures, i.e. 200, 250, 273, 300 and 350 K. The analyses on structural flexibility and conformational distribution indicated that the structure of the SARS-CoV-2 RBD was more stable than that of the SARS-CoV RBD at all investigated temperatures. Then, molecular mechanics Poisson-Boltzmann surface area and solvated interaction energy approaches were combined to estimate the differences in binding affinity of SARS-CoV and SARS-CoV-2 RBDs to ACE2; it is found that the binding ability of ACE2 to the SARS-CoV-2 RBD was stronger than that to the SARS-CoV RBD at five temperatures, and the main reason for promoting such binding differences is electrostatic and polar interactions between RBDs and ACE2. Finally, the hotspot residues facilitating the binding of SARS-CoV and SARS-CoV-2 RBDs to ACE2, the key differential residues contributing to the difference in binding and the interaction mechanism of differential residues that exist at all investigated temperatures were analyzed and compared in depth. The current work would provide a molecular basis for better understanding of the high infectiousness of SARS-CoV-2 and offer better theoretical guidance for the design of inhibitors targeting infectious diseases caused by SARS-CoV-2.
温度在严重急性呼吸综合征冠状病毒（SARS-CoV）和 SARS-CoV-2 的存活和传播中起着重要作用。为了在原子水平上揭示 SARS-CoV 和 SARS-CoV-2 受体结合域（RBD）与血管紧张素转换酶 2（ACE2）在不同温度下的结合差异，在五个选定温度下，即 200、250、273、300 和 350 K，对 SARS-CoV 和 SARS-CoV-2 RBD-ACE2 复合物进行了 20 次分子动力学模拟。结构柔性和构象分布的分析表明，在所有研究温度下，SARS-CoV-2 RBD 的结构比 SARS-CoV RBD 更稳定。然后，将分子力学泊松-玻尔兹曼表面区域和溶剂化相互作用能方法相结合，以估计 SARS-CoV 和 SARS-CoV-2 RBD 与 ACE2 的结合亲和力差异；发现 ACE2 与 SARS-CoV-2 RBD 的结合能力在五个温度下均强于与 SARS-CoV RBD 的结合能力，促进这种结合差异的主要原因是 RBD 与 ACE2 之间的静电和极性相互作用。最后，深入分析和比较了促进 SARS-CoV 和 SARS-CoV-2 RBD 与 ACE2 结合的热点残基、导致结合差异的关键差异残基以及在所有研究温度下存在的差异残基的相互作用机制。目前的工作将为更好地理解 SARS-CoV-2 的高传染性提供分子基础，并为针对 SARS-CoV-2 引起的传染病设计抑制剂提供更好的理论指导。
