Does SARS-CoV-2 Bind to Human ACE2 Stronger Than SARS-CoV?

Hoang Linh Nguyen, Pham Dang Lan, Nguyen Quoc Thai, Daniel A. Nissley, Edward P. O'Brien, and Mai Suan Li

The Journal of Physical Chemistry B Just Accepted Manuscript
DOI: 10.1021/acs.jpcb.0c04511

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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 8,096 confirmed cases in more than 25 countries in 2002–2003. 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-PB) more strongly than 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 the SARS-CoV (SARS-CoV-RBD) and of SARS-CoV-2 (SARS-CoV-2-RBD) interacts with a human ACE2 peptidase domain (ACE2-PB) 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 coarse-grained simulation, SARS-CoV-2-RBD was associated with ACE2-PD stronger than SARS-CoV-RBD, 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.