Molecular dynamics analysis of fast-spreading severe acute respiratory syndrome coronavirus 2 variants and their effects in 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 to contain the spread of the disease in many countries has given rise to novel viral variants with increased transmissibility. However, key questions about how quickly the variants can spread and whether they can cause a more severe disease remain unclear. Herein, we performed a structural investigation using molecular dynamics simulations and determined dissociation constant (KD) values using surface plasmon resonance (SPR) assays of three fast-spreading SARS-CoV-2 variants, Alpha, Beta and Gamma ones, as well as genetic factors in the 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 variants 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 wild-type.

Severe Acute Respiratory Syndrome Coronavirus 2 Variants of Concern: A Perspective for Emerging More Transmissible and Vaccine-Resistant Strains

“…In relation to the Spike of SARS-CoV-2 WT , D614G Spike trimer presents comparable k a and k d rates of ~1.6 × 10 5 M −1 s −1 and ~1.7 × 10 −4 s −1 , resulting in similar binding affinity to hACE2 (K D SARS-CoV−2 /K D D614G of ~1:1) [60]. Our previous studies have shown that the Spike protein of SARS-CoV-2 Alpha , SARS-CoV-2 Beta and SARS-CoV-2 Gamma presents comparable values of binding affinity to hACE as SARS-CoV-2 WT , with K D values ranging from 1.1 to 1.8 nM [54], but higher affinity than the trimeric form of the Spike protein of SARS-CoV-2 WT (K D values ~16 nM) [55]. A similar result was also observed for the Omicron variant that has higher affinity to hACE than the wild type but comparable values of binding affinity to hACE as SARS-CoV-2 Beta [66].…”

“…Even after the vaccination rates in the United States, United Kingdom, Germany and Japan surpassed 50%, all these countries had a significant increase in the number of cases and deaths. These data are explained by the emergence of novel variants of SARS-CoV-2 associated with lower efficiency of neutralizing antibodies [54,141]. For those countries that surpassed 60% of the population vaccinated with the first dose, such as Germany and the United Kingdom, the number of deaths was remarkably lower than rates seen during the first wave.…”

Molecular dynamics simulations of the spike trimeric ectodomain of the SARS-CoV-2 Omicron variant: structural relationships with infectivity, evasion to immune system and transmissibility

“…In SARS-CoV-2 VOCs, the mutations in the Spike protein often cause an increase in the binding affinity to hACE2 [15,16]. However, when these binding affinity values are compared between VOCs, they are within the same order of magnitude [17][18][19][20], suggesting that transmissibility, viral load and lethality may also be related to other molecular factors, such as: (1) an increase of RBD up dispositions in Spike [18,19,21]; (2) immune system evasion [22][23][24][25][26]; and (3) level of exposure of the furin cleavage site to proteases [27][28][29].…”

SARS-CoV-2 variants impact RBD conformational dynamics and ACE2 accessibility

“…This rate constant reflects the efficiency with which protein–protein collisions lead to a bound state. While a couple of studies show no significant impact ( 91 , 95 ), most show that the variants lead to a substantial increase in k on , reflecting an increase in RBD accessibility to ACE2 ( 92 – 94 , 96 , 101 ). We propose that this can be explained by the significant changes in RBM conformational dynamics that we have here described, where mutations lead to a decrease in prevalence of the closed state, favoring binding.…”