Structural dynamics of SARS-CoV-2 variants: A health monitoring strategy for anticipating Covid-19 outbreaks

Abstract

Objectives: the Covid-19 pandemic has been marked by sudden outbreaks of SARS-CoV-2 variants harboring mutations in both the N-terminal (NTD) and receptor binding (RBD) domains of the spike protein. The goal of this study was to predict the transmissibility of SARS-CoV-2 variants from genomic sequence data.

Methods: we used a target-based molecular modeling strategy combined with surface potential analysis of the NTD and RBD.

Results: we observed that both domains act synergistically to ensure optimal virus adhesion, which explains why most variants exhibit concomitant mutations in the RBD and in the NTD. Some mutation patterns affect the affinity of the spike protein for ACE-2. However, other patterns increase the electropositive surface of the spike, with determinant effects on the kinetics of virus adhesion to lipid raft gangliosides. Based on this new view of the structural dynamics of SARS-CoV-2 variants, we defined an index of transmissibility (T-index) calculated from kinetic and affinity parameters of coronavirus binding to host cells. The T-index is characteristic of each variant and predictive of its dissemination in animal and human populations.

Conclusions: the T-index can be used as a health monitoring strategy to anticipate future Covid-19 outbreaks due to the emergence of variants of concern.

Keywords: ACE-2; Coronavirus; Electrostatic surface potential; Ganglioside; Lipid raft; SARS-CoV-2; Virus-host interactions; receptor.

Fig. 1

Topology of SARS-CoV-2 spike trimer in the closed and open states. A. The closed conformation of SARS-CoV-2 spike trimer is retrieved from pdb file 7VSB. The trimer is viewed from the top, facing the host cell membrane (upper panel). Subunits A, B, and C of the pdb file are colored in cyan, yellow and purple, respectively. The white asterisk on the RBD of chain C indicates the center of the ACE-2 binding motif around residue Y-489. The electrostatic surface potential of the spike is represented in the lower panel. The NTD of the A chain is bound to a GM1 lipid raft. B. The open conformation of SARS-CoV-2 spike trimer is retrieved from pdb file 7DK3. The RBD of the C chain has moved in the direction of the NTD of chain A so that the lining residues that bind to ACE-2 are now rejected at the periphery of the spike (upper panel, white asterisk). Since ACE-2 is a lipid raft associated protein, an ACE-2 raft may thus bind and coalesce with the GM1 raft already bound to the NTD of chain A, increasing the probability of a functional contact between the spike and the ACE-2 receptor. Note that at this stage, all three NTDs display an electropositive surface potential consistent with the recruitment of several lipid rafts around the viral spike (lower panel). During this lipid raft controlled process, the closed state moves from an ACE-2 inaccessible to an ACE-2 accessible topology (open state). The color scale for the electrostatic surface potential (negative in red, positive in blue, neutral in white) is indicated. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.).

Fig. 2

Molecular mechanisms of RBD binding to ACE-2. A. Overall view of the RBD-ACE-2 complex showing the three main forces of stabilization: van der Waals, electrostatic and hydrogen bonding. B. Focus on van der Waals forces illustrated by Y489 and Q498 from the RBD interacting with T27 and L45 from ACE-2, respectively through London forces and CH-π stacking. C. Electrostatic interactions involving residues D30 and K31 from ACE-2 and K417 and E-484 from the RBD. D. A network of hydrogen bonds linking residues D-38 from ACE-2, and Y449 and Q498 from the RBD. (For interpretation of the references to color in this figure, the reader is referred to the web version of this article.)

Fig. 3

ACE-2 and RBD electrostatic surface potential. A. RBD-ACE-2 complex. The yellow line shows the limit between the RBD and ACE-2 in the complex. B. Separate views of ACE-2 and of the RBD. Electrostatic attraction is represented by solid arrows, whereas electrostatic repulsion is indicated by dashed arrows. C. Bottom view of ACE-2 and top view of the RBD after 90° rotation. The electrostatic surface potential is represented in three colors: blue, electropositive, red, electronegative, white, neutral. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

Electrostatic surface potential of the NTD and a GM1 lipid raft. A. NTD-GM1 lipid raft complex. B. Separate views of the NTD and of the GM1 raft. C. A rotation of 90° of the NTD shows that its flat surface in contact with the raft has several electropositive regions around a central negative area corresponding to amino acid residues 154–156. The position 69–70 and 144 are indicated because these three amino acid residues are deleted in the UK variant of SARS-CoV-2. The GM1 lipid raft displays a homogenous electronegative surface.

Fig. 5

Impact of the N501Y mutation (UK variant) of ACE-2 recognition. A. Overall view of the molecular complex between ACE-2 and the mutant RBD with the N501Y mutation. The mutant tyrosine-501 residue is in close contact with tyrosine-41 and lysine-353 of ACE-2. B. Electrostatic surface potential of the Wuhan (wt) and UK variant RBD displaying the N501Y mutation. The yellow disk indicates position 501 in both wt and mutant spike proteins. C. Interactions of asparagine-501 with ACE-2 residues 41 and 353. Although the three residues lie in the same area, they interact chiefly by van der Waals forces (energy of interaction −20.6 kJ. mol⁻¹). D. Network of hydrogen bonds and CH-π stacking involving the mutant residue tyrosine-501 of the UK variant (energy of interaction −25.4 kJ. mol⁻¹). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 6

Impact of deletions 69–70 and 144 (B.1.1.7 UK variant) on the surface potential of the NTD. The electrostatic surface potential of the B.1.1.7 variant NTD shows important electronic redistribution compared with the Wuhan B.1 NTD. The relative intensity of blue and red colors in the central region of the NTD (yellow frame) is indicated in the histograms. Changes in electrostatic potential affect four distinct zones numbered from 1 to 4. The deletions located in zones 2 and 3 increase the surface potential of the NTD. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 7

Impact of mutations K417T, E484K and N501Y (Brazil B.1.1.248 variant) on ACE-2 recognition. A. Overall view of the molecular complex between ACE-2 and the Brazil B.1.1.248 RBD with the three mutations K417T, E484K and N501Y. Both lysine-484 and tyrosine-501 interact closely with ACE-2, whereas threonine-417 has no contact with the receptor. B. The side chain of lysine-484 establishes stabilizing van der Waals interactions with methylene groups of lysine-31 (cyan disk) and a hydrogen bond with tyrosine-83 of ACE-2. C. Electrostatic surface potential of the Wuhan B.1 RBD with positions 417, 484 and 501 indicated. D. Electrostatic surface potential of the Brazil B.1.1.248 RBD (mutations 417, 484 and 501 are indicated). K417T is associated with a loss of positive charge which results in decreased interaction of the RBD with ACE-2. N501Y, which slightly increases the local surface potential, also increases ACE-2 binding. Finally, E484K induces an inversion of the surface potential, which improves ACE-2 recognition.

Fig. 8

Impact of mutations L18F, T20N, P26S, D138Y, and R190S on the NTD (Brazil B.1.1.248 variant). The electrostatic surface potential of the Brazil B.1.1.248 NTD shows important changes in charge distribution compared with the Wuhan B.1 NTD. Changes in electrostatic potential affect five distinct zones numbered from 1 to 5. The relative intensity of blue and red colors in regions 1 and 4 (yellow frames) is indicated in the histograms. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 9

Comparative analysis of the NTD and RBD surface potential in SARSCoV-2 variants. This analysis illustrates the evolution of the surface potential in both the NTD and the RBD of current circulating SARS-CoV-2 strains over the world. There is a clear tendency to decrease electronegative spots and increase electropositive surfaces. The surface potential values (positive/negative) are indicated (see legend of Table 2 for further details).