The SARS-CoV-2 Exerts a Distinctive Strategy for Interacting with the ACE2 Human Receptor

Abstract

The COVID-19 disease has plagued over 200 countries with over three million cases and has resulted in over 200,000 deaths within 3 months. To gain insight into the high infection rate of the SARS-CoV-2 virus, we compare the interaction between the human ACE2 receptor and the SARS-CoV-2 spike protein with that of other pathogenic coronaviruses using molecular dynamics simulations. SARS-CoV, SARS-CoV-2, and HCoV-NL63 recognize ACE2 as the natural receptor but present a distinct binding interface to ACE2 and a different network of residue-residue contacts. SARS-CoV and SARS-CoV-2 have comparable binding affinities achieved by balancing energetics and dynamics. The SARS-CoV-2-ACE2 complex contains a higher number of contacts, a larger interface area, and decreased interface residue fluctuations relative to the SARS-CoV-ACE2 complex. These findings expose an exceptional evolutionary exploration exerted by coronaviruses toward host recognition. We postulate that the versatility of cell receptor binding strategies has immediate implications for therapeutic strategies.

Keywords: ACE2; SARS-CoV-2; coronavirus evolution; molecular dynamics; protein–protein complex; virus–host interactions.

Figure 1

Analysis of RBD–ACE2 interactions based on the molecular dynamics (MD) trajectories. COVID-19, SARS-2002, HCoV-NL63, and MERS are colored blue, red, green, and purple, respectively. (A) Histograms of the RBD–ACE2 interaction scores throughout the simulation trajectory. Darker color represents 75% of all frames; (B) the score values along the simulation trajectory, smoothed along the elapsed time; (C) Venn diagram of ACE2 interacting residues for COVID-19, SARS-2002, and HCoV-NL63. An ACE2 residue is considered as part of the interface if one of its atoms is within 4 Å from any RBD atom in at least 10% of the 10,000 MD simulation frames; (D) overlay of 50 snapshots for each of the three RBDs. The ACE2 is in surface representation (gray). The frames were aligned using the N-terminal fragment of the ACE2 that contains the two helices participating in the RBDs binding.

Figure 2

Interaction interfaces of RBD–ACE2. A residue is considered as part of the interface if one of its atoms is within 4 Å from any atom of the other partner in at least 30% of the 10,000 MD simulation frames. (A) The interface residue side-chain heavy atoms that vary between COVID-19 (blue) and SARS-2002 (red) are shown with ball-and-stick representations. ACE2 is colored gray; (B) the contacts difference plot between COVID-19 and SARS-2002 (left). A residue–residue contact frequency (CF) is defined as the fraction of MD trajectory frames in which the contact appears. The contacts with 50% greater CF in COVID-19 RBD–ACE2 vs. SARS-2002 RBD–ACE2 are colored blue. The contacts with 50% greater CF in SARS-2002 RBD–ACE2 vs. COVID-19 RBD–ACE2 are colored red. Similar interface-residue CFs (<50% difference) in both RBDs are colored gray. The residue numbering is according to COVID-19 (RefSeq: YP_009724390.1). Difference plots for interface residue CFs that are in the interface for ACE2 (middle) and RBD (right); (C) zooms on the interface contacts unique to each virus. The COVID-19 patches are colored blue with the corresponding ACE2 patches in cyan, and the SARS-2002 patch is in red with the corresponding ACE2 patch in orange.

Figure 3

Dynamics of the RBD domains. (A–C) The dynamics of COVID-19 and SARS2002, with a comparison to a designed SARS mutant are shown. The graphs show the root-mean-square fluctuation (RMSF) of each residue along the simulation trajectory with respect to the structure with minimum energy. The residue numbers are according to COVID-19 numbering (RefSeq: YP_009724390.1). The top graph (A) compares COVID-19 with SARS-2002. The middle graph (B) compares COVID-19 with SARS-designed. The bottom graph (C) compares SARS-2002 with SARS-designed. For all three graphs, the positions highlighted in red or blue indicate those that have an increase or decrease, respectively, of 50% RMSF with respect to the comparison graph. The contact positions are written in gray, with solid vertical lines denoting the contact residues that exist in both of the comparison structures, and dashed vertical lines denote the contact residues that exist in only one of the comparison structures; (D) the RMSF mapped onto the RBD structure (red—more rigid, blue—more flexible); (E) the schematic representation of ACE2 binding strategies by COVID-19, SARS-2002, and HCoV-NL63 RBDs.