Mutation in a SARS-CoV-2 Haplotype from Sub-Antarctic Chile Reveals New Insights into the Spike's Dynamics

Jorge González-Puelma, Jacqueline Aldridge, Marco Montes de Oca, Mónica Pinto, Roberto Uribe-Paredes, José Fernández-Goycoolea, Diego Alvarez-Saravia, Hermy Álvarez, Gonzalo Encina, Thomas Weitzel, Rodrigo Muñoz, Álvaro Olivera-Nappa, Sergio Pantano, Marcelo A Navarrete, Jorge González-Puelma, Jacqueline Aldridge, Marco Montes de Oca, Mónica Pinto, Roberto Uribe-Paredes, José Fernández-Goycoolea, Diego Alvarez-Saravia, Hermy Álvarez, Gonzalo Encina, Thomas Weitzel, Rodrigo Muñoz, Álvaro Olivera-Nappa, Sergio Pantano, Marcelo A Navarrete

Abstract

The emergence of SARS-CoV-2 variants, as observed with the D614G spike protein mutant and, more recently, with B.1.1.7 (501Y.V1), B.1.351 (501Y.V2) and B.1.1.28.1 (P.1) lineages, represent a continuous threat and might lead to strains of higher infectivity and/or virulence. We report on the occurrence of a SARS-CoV-2 haplotype with nine mutations including D614G/T307I double-mutation of the spike. This variant expanded and completely replaced previous lineages within a short period in the subantarctic Magallanes Region, southern Chile. The rapid lineage shift was accompanied by a significant increase of cases, resulting in one of the highest incidence rates worldwide. Comparative coarse-grained molecular dynamic simulations indicated that T307I and D614G belong to a previously unrecognized dynamic domain, interfering with the mobility of the receptor binding domain of the spike. The T307I mutation showed a synergistic effect with the D614G. Continuous surveillance of new mutations and molecular analyses of such variations are important tools to understand the molecular mechanisms defining infectivity and virulence of current and future SARS-CoV-2 strains.

Keywords: Covid19; SARS-CoV2; variant.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Phylodynamic evolution and new daily cases incidence in the Magallanes Region. The phylodynamic tree depicts the number of mutations of isolated genomes during the study period in the Magellanes Region; colors refer to Nextstrain clade classification (upper left corner) of analyzed strains. Clade defining mutations: 19A Wuhan Strain; 19B: ORF8 251S; 20A: Spike 614G; 20B: derived from 20A bearing Nuclocapsid 203K, N204R and ORF14 50N; 20C: derived from 20A bearing ORF3a 57H and ORF1a 265I. Histogram chart showing daily incidence rates of confirmed COVID-19 cases in the Magallanes Region.
Figure 2
Figure 2
Geodynamic evolution of clades and spike 307 mutation. (a) Shows the geolocation of study sites in the Magallanes Region in Chile’s extreme south (N, Puerto Natales; A, Punta Arenas; R, Porvenir; W, Puerto Williams). (b) Demonstrates the distribution of mutations of spike protein at genomic position 22,482 and clades (Nextstrain classification) at the four study sites. Colored dots represent individual cases analyzed by targeted sequencing and whole genome sequencing (WGS). (c) Shows the relative frequency of spike protein mutations at position 307.
Figure 3
Figure 3
Mutational effect and frequency across epidemic phases. (a) Shows the frequency of amino acid changes induced by non-synonymous mutations. (b) Depicts the genomic position and relative frequency of both synonymous and non-synonymous mutations during the three epidemic phases the world’s global relative frequency included as a reference.
Figure 4
Figure 4
Structure and dynamics of the soluble part of SARS-CoV-2 spike. (a) Global architecture of the homotrimer. The foremost protomer is shown in cartoon representation, while the other two are shown by solvent accessible surface. The S1 segment is colored by structural domains discussed in the main text (green: N-terminal domain, NTD; red: receptor binding domain, RBD; blue: gear-like domain, GLD). The two amino acids mutated are shown in space-filling representation and the amino acids in the furin loop are shown as sticks. (b) Extreme projections of the main component of the motion in the S1 segment. The black tube corresponds to the average position of the protein backbone. The direction of the motion is indicated by lines changing from red to blue color. (c) Upper left panel: close up on the amino acids surrounding T307 and F306 in the cryo–electron microscopy structure used as the starting configuration. Upper right panel: Final conformation of the molecular dynamics simulation with the side chains of I307 and F306 in close contact. Lower panel: spike protein alignment around the conserved hydrophobic cluster (L48, L276, V289) interacting with F306 in different β-coronaviruses.
Figure 5
Figure 5
Proposed molecular dynamic of spike protein. (a) Schematic representation depicts a proposed gear-like mechanism for the molecular dynamic of the S1 subunit in which the rotation of gear-like domain (GLD) is accompanied by the solidary movement of the N-terminal and receptor binding domains (NTD and RBD respectively). (b) Superposition of spike experimental structures in the all-RBD-down state captured with different rotations of the GLD, depicting a counter-clockwise rotation of the gear-like domain. The GLD is shown in cartoon representation and NTD and RBD from the wild type protein are shown in solvent accessible surface. In blue: SARS-CoV-2 S wild type (WT) (pdb: 6XR8), yellow: SARS-CoV-2 S D614G (pdb: 6XS6), red: infectious bronchitis coronavirus (pdb: 6CV0). (c) Superposition of spike experimental structures in the all-RBD-down, depicting domain movements between pH 5.5 and 4.0. In purple: spike at pH 4.0 (pdb: 6XLU), calypso: spike at pH 5.5 (pdb: 6XM5). F306 are shown as sticks. NTD: N-terminal domain, RBD: receptor binding domain, GLD: gear-like domain.

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