Infection and replication of SARS CoV-2 (the virus that causes COVID-19) requires entry to the interior of host cells. In humans, a Protein-Protein Interaction (PPI) between the SARS CoV-2 Receptor-Binding Domain (RBD) and the extracellular peptidase domain of ACE2, on the surface of cells in the lower respiratory tract, is an initial step in the entry pathway. Inhibition of the SARS CoV-2 RBD / ACE2 PPI is currently being evaluated as a target for therapeutic and/or prophylactic intervention. However, relatively little is known about the molecular underpinnings of this complex. Employing multiple computational platforms, we predicted hot-spot residues in a positive control PPI (PMI / MDM2) and the CoV-2 RBD/ACE2 complex. Computational alanine scanning mutagenesis was performed to predict changes in Gibbs free energy that are associated with mutating residues at the positive control (PMI/MDM2) or SARS RBD/ACE2 binding interface to alanine. Additionally, we used the Adaptive Poisson-Boltzmann Solver to calculate macromolecular electrostatic surfaces at the interface of the positive control PPI and SARS CoV-2 / ACE2 PPI. Collectively, this study illuminates predicted hot-spot residues, and clusters, at the SARS CoV-2 RBD / ACE2 binding interface, potentially guiding the development of reagents capable of disrupting this complex and halting COVID-19.

中文翻译：

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SARS-CoV-2受体结合域/ ACE2复合体的计算热点分析。

SARS CoV-2（引起COVID-19的病毒）的感染和复制需要进入宿主细胞内部。在人类中，下呼吸道细胞表面上SARS CoV-2受体结合域（RBD）与ACE2的细胞外肽酶域之间的蛋白质相互作用（PPI）是进入的第一步途径。目前正在评估SARS CoV-2 RBD / ACE2 PPI的抑制作用，作为治疗和/或预防干预的目标。但是，对这种复合物的分子基础知之甚少。我们使用多个计算平台，预测了阳性对照PPI（PMI / MDM2）和CoV-2 RBD / ACE2复合物中的热点残基。进行计算丙氨酸扫描诱变以预测吉布斯自由能的变化，该变化与阳性对照（PMI / MDM2）或SARS RBD / ACE2与丙氨酸的结合界面处的突变残基相关。此外，我们使用了自适应Poisson-Boltzmann解算器来计算阳性对照PPI和SARS CoV-2 / ACE2 PPI界面处的高分子静电表面。总的来说，这项研究阐明了SARS CoV-2 RBD / ACE2结合界面上预测的热点残基和簇，潜在地指导了能够破坏这种复合物并阻止COVID-19的试剂的开发。我们使用自适应Poisson-Boltzmann解算器来计算阳性对照PPI和SARS CoV-2 / ACE2 PPI界面处的高分子静电表面。总的来说，这项研究阐明了SARS CoV-2 RBD / ACE2结合界面上预测的热点残基和簇，潜在地指导了能够破坏这种复合物并阻止COVID-19的试剂的开发。我们使用自适应Poisson-Boltzmann解算器来计算阳性对照PPI和SARS CoV-2 / ACE2 PPI界面处的高分子静电表面。总的来说，这项研究阐明了SARS CoV-2 RBD / ACE2结合界面上预测的热点残基和簇，潜在地指导了能够破坏这种复合物并阻止COVID-19的试剂的开发。