Does SARS-CoV-2 Bind to Human ACE2 More Strongly Than Does SARS-CoV?

Abstract

The 2019 novel coronavirus (SARS-CoV-2) epidemic, which was first reported in December 2019 in Wuhan, China, was declared a pandemic by the World Health Organization in March 2020. Genetically, SARS-CoV-2 is closely related to SARS-CoV, which caused a global epidemic with 8096 confirmed cases in more than 25 countries from 2002 to 2003. Given the significant morbidity and mortality rate, the current pandemic poses a danger to all of humanity, prompting us to understand the activity of SARS-CoV-2 at the atomic level. Experimental studies have revealed that spike proteins of both SARS-CoV-2 and SARS-CoV bind to angiotensin-converting enzyme 2 (ACE2) before entering the cell for replication. However, the binding affinities reported by different groups seem to contradict each other. Wrapp et al. ( Science 2020 , 367 , 1260–1263) showed that the spike protein of SARS-CoV-2 binds to the ACE2 peptidase domain (ACE2-PD) more strongly than does SARS-CoV, and this fact may be associated with a greater severity of the new virus. However, Walls et al. ( Cell 2020 , 181 , 281–292) reported that SARS-CoV-2 exhibits a higher binding affinity, but the difference between the two variants is relatively small. To understand the binding mechnism and experimental results, we investigated how the receptor binding domain (RBD) of SARS-CoV (SARS-CoV-RBD) and SARS-CoV-2 (SARS-CoV-2-RBD) interacts with a human ACE2-PD using molecular modeling. We applied a coarse-grained model to calculate the dissociation constant and found that SARS-CoV-2 displays a 2-fold higher binding affinity. Using steered all-atom molecular dynamics simulations, we demonstrate that, like a coarse-grained simulation, SARS-CoV-2-RBD was associated with ACE2-PD more strongly than was SARS-CoV-RBD, as evidenced by a higher rupture force and larger pulling work. We show that the binding affinity of both viruses to ACE2 is driven by electrostatic interactions.

In silico investigation of critical binding pattern in SARS-CoV-2 spike protein with angiotensin-converting enzyme 2

“…This finding was in agreement with other studies. Nguyen et al reported that the binding affinity of SARS-CoV-2 to ACE2 is a twofold higher, and the binding affinity of both viruses to ACE2 is driven by electrostatic interactions 38 . Consistent with our results, Wrapp et al indicated that the binding affinity of SARS-CoV-2 to ACE-2 is ~ 10- to 20 folds higher than SARS-CoV 35 .…”

Critical interactions for SARS-CoV-2 spike protein binding to ACE2 identified by machine learning

“…A number of previous molecular dynamics (MD) studies have compared the dynamics of SARS-CoV and SARS-CoV-2 complexes with ACE2, 21,[23][24][25][26] including a study of the full-length complex in the context of the cellular membrane. 27 It was shown that the SARS-CoV-2 complex is more stable, as measured by root-mean-square deviation (RMSD) and the increased number contacts between RBD and ACE2.…”

Investigation of Critical Binding Pattern in SARS-CoV-2 Spike Glycoprotein with Angiotensin-Converting Enzyme 2: An in Silico Analysis 

“…This nding was in agreement with other studies. Nguyen et al reported that the binding a nity of SARS-CoV-2 to ACE2 is a 2-fold higher, and the binding a nity of both viruses to ACE2 is driven by electrostatic interactions 25 . Consistent with our results, Wrapp et al indicated that the binding a nity of SARS-CoV-2 to ACE-2 is ~ 10-to 20 folds higher than SARS-CoV 22 .…”