Molecular Dynamics Analysis of Fast-Spreading Severe Acute Respiratory Syndrome Coronavirus 2 Variants and Their Effects on the Interaction with Human Angiotensin-Converting Enzyme 2

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is evolving with mutations in the spike protein, especially in the receptor-binding domain (RBD). The failure of public health measures in some countries to contain the spread of the disease has given rise to novel viral variants with increased transmissibility. However, key questions about how quickly the variants can spread remain unclear. Herein, we performed a structural investigation using molecular dynamics simulations and determined dissociation constant (K D) values using surface plasmon resonance assays of three fast-spreading SARS-CoV-2 variants, alpha, beta, and gamma, as well as genetic factors in host cells that may be related to the viral infection. Our results suggest that the SARS-CoV-2 variants facilitate their entry into the host cell by moderately increased binding affinities to the human ACE2 receptor, different torsions in hACE2 mediated by RBD variants, and an increased spike exposure time to proteolytic enzymes. We also found that other host cell aspects, such as gene and isoform expression of key genes for the infection (ACE2, FURIN, and TMPRSS2), may have few contributions to the SARS-CoV-2 variant infectivity. In summary, we concluded that a combination of viral and host cell factors allows SARS-CoV-2 variants to increase their abilities to spread faster than the wild type.

Cooperative and structural relationships of the trimeric Spike with infectivity and antibody escape of the strains Delta (B.1.617.2) and Omicron (BA.2, BA.5, and BQ.1)

“…Our previous studies showed that the Spike VOCs have similar binding affinities to hACE2, but these are higher than that of Spike WT (de Souza, de Freitas Amorim, Guardia, Dos Santos, Dos Santos, et al, 2022; de Souza, de Freitas Amorim, Guardia, Dos Santos, Ulrich, et al, 2022). Previously results have shown that substitutions K417N, S477N, T478K, E484K and N501Y cause an increase in binding affinity between RBD and hACE2 (Chen et al, 2021; de Souza, de Freitas Amorim, Guardia, Dos Santos, Dos Santos, et al, 2022; de Souza, de Freitas Amorim, Guardia, Dos Santos, Ulrich, et al, 2022; de Souza et al, 2021; Tian et al, 2021). The substitutions L452R and F486V found in BA.4 and BA.5 play a key role in the decrease of neutralizing antibody recognition (Cao, Yisimayi, et al, 2022; Tuekprakhon et al, 2022).…”

“…When SARS-CoV-2 variants are compared, mutations can be found in any gene, but a higher number of mutations concentrate in the gene region that encodes the Spike protein (de Souza, de Freitas Amorim, Guardia, Dos Santos, Ulrich, et al, 2022). Spike is a homotrimer anchored in the viral membrane composed by S1 and S2 subunits, each performing a different role in the viral infection (de Souza, de Freitas Amorim, Guardia, Dos Santos, Dos Santos, et al, 2022; de Souza, de Freitas Amorim, Guardia, Dos Santos, Ulrich, et al, 2022). The S1 subunit contains the N-terminal domain (NTD), the receptor binding domain (RBD) that play key roles in recognition of the hACE2, SD1 and SD2 domains (de Souza, de Freitas Amorim, Guardia, Dos Santos, Dos Santos, et al, 2022; de Souza, de Freitas Amorim, Guardia, Dos Santos, Ulrich, et al, 2022; Sironi et al, 2020; Souza et al, 2020).…”

“…Spike is a homotrimer anchored in the viral membrane composed by S1 and S2 subunits, each performing a different role in the viral infection (de Souza, de Freitas Amorim, Guardia, Dos Santos, Dos Santos, et al, 2022; de Souza, de Freitas Amorim, Guardia, Dos Santos, Ulrich, et al, 2022). The S1 subunit contains the N-terminal domain (NTD), the receptor binding domain (RBD) that play key roles in recognition of the hACE2, SD1 and SD2 domains (de Souza, de Freitas Amorim, Guardia, Dos Santos, Dos Santos, et al, 2022; de Souza, de Freitas Amorim, Guardia, Dos Santos, Ulrich, et al, 2022; Sironi et al, 2020; Souza et al, 2020). The RBD may be present in two conformational states, up or down.…”

“…Zhang et al, 2022). In addition, transmembrane Serine Protease 2 (TMPRSS2) and Cathepsin isoforms also recognize and cleave the S2’ site (KPSKR 815 ↓) (Bosch et al, 2008; de Souza, de Freitas Amorim, Guardia, Dos Santos, Dos Santos, et al, 2022; Essalmani et al, 2022; Hoffmann et al, 2020; Zang et al, 2020; M.-M. Zhao et al, 2022). After hACE2 interaction and S2’ cleavage, the S2 subunit undergoes a major structural change to expose the fusion loop, which mediates the fusion of virus envelope and host cell membrane, allowing the formation of a pore for the release of viral RNA into the cell cytoplasm (Jackson et al, 2022).…”

Molecular Dynamics Simulations Suggest Sars-Cov-2 3clpro Mutations in Beta and Omicron Variants do not Alter Binding Affinities for Cleavage Sites of Non-Structural Proteins

“…Among the molecular targets, the Spike protein and the 3-chymotrypsin-like protease (3CLpro or Mpro, SARS-CoV-2 main protease) play key roles in vaccine and drug designs, respectively [14][15][16][17][18][19]. In particular, the 3CLpro cleaves 13 sites of two polyproteins, pp1a and pp1ab, which are results from translation of the genomic mRNA.…”