Evaluation of the Effect of D614g, N501y and S477n Mutation in Sars-Cov-2 through Computational Approach

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes an outbreak of COVID-19 disease in humans with the aid of spike protein. It consists of a receptor-binding domain (RBD) that recognizes and binds to the host receptor angiotensin-converting enzyme 2 (ACE2). The aim of this study was to examine the mutational effect of spike protein on the sequence through an interaction study of the mutant spike protein and the human ACE2 protein at the structural level. A total of 17,227 spike proteins from Asia, Africa, Europe, Oceania, South America, and North America were compared to the Wuhan spike protein reference sequence (Wuhan-Hu-1). The structural and stability implications of D614G, N501Y, and S477N mutations were evaluated. The binding affinity between mutated RBD and human ACE2 protein was also studied. The D614G mutation may have originated in Germany, Europe based on the date of the first sample collection report. It is now widely circulated all over the world with most occurrences in North America. The mutations N501Y and S477N may have originated from Oceania based on the date of the first sample collection report and also have the highest occurrences in Oceania. Based on the computational analysis of mutational effects, the D614G, N501Y, and S477N mutations decreased stability and were tolerated. For disease propensity prediction, N501Y was more prone to disease compared to D614G, while S477N was not prone to disease. The mutation of D to G at position 614 and S to N at position 477 for secondary structure prediction shows no changes in secondary structure while remaining in the coil region, whereas the mutation of N to Y at position 501 changes from coil structure to extended strand. N501Y mutation has a higher affinity to human ACE2 protein compared to D614G and S477N based on a docking study. D614G spike mutation was identified to exist between the two hosts based on a comparison of SARS-CoV-2 derived between the mink and human. Further research is needed on the link between the mink mutation N501T and the mutation N501Y in humans, which has evolved as a separate variant.

SARS-CoV-2 complete genome sequencing from the Italian Campania region using a highly automated next generation sequencing system

“…Selected mutations such as the D614G might provide an advantage to the virus by increasing the cellular infectivity and virus transmissibility. Recently, a N501Y mutation on the Spike gene has been reported [ 24 ] showing a higher affinity to human ACE2 protein as compared to D614G. The surveillance on circulating strain is highly relevant today because the novel variants, with multiple mutations in their spike glycoproteins, are key targets of virus-neutralizing antibodies and raise the concern of vaccine efficacy against the novel strains.…”

Computational Investigation of Increased Virulence and Pathogenesis of SARS-CoV-2 Lineage B.1.1.7

“…5 The N501Y mutation occurring in the RDB of spike protein is proposed to increase the binding affinity of the spike protein to murine and human angiotensin-converting enzyme-2 (ACE-2) receptors. 6,7 Accumulation of high mutation rates within short time periods suggest that this variant might not have emerged from gradual accumulation of mutations but could have arisen by selection pressure through intrapatient virus genetic diversity after convalescent plasma treatment. 8 The probable sources that has given rise to this variant with multiple mutations can be explained by three possible processes namely i) prolonged SARS-CoV-2 infection in immune-deficient/suppressed patients leading to accumulation of immune evading mutations at higher rate; ii) adaptation process of SARS-CoV-2 as in the case of Y453F mutation or 69/70 deletions that have occurred in different animal species followed by zoonotic transmission to human host and iii) antibody-mediated selective pressure creating multiple genetic changes in SARS-CoV-2 through direct selection or by genetic hitchhiking.…”

The coSIR model predicts effective strategies to limit the spread of SARS-CoV-2 variants with low severity and high transmissibility

“…Although SARS-CoV-2 has a relatively low genomic diversity [4] due to its proofreading mechanisms [5], natural selection can accelerate the rapid spread of environmentally favourable variants. Since the outbreak of the epidemic, novel SARS-CoV-2 strains have been described in many studies and reports [6][7][8][9][10][11][12][13]. While new strains with higher transmissibility emerged frequently-the D614G mutant replaced the original virus strain as the majority in just four months [6], and the N501Y mutant was approximately 70% more infectious [13]-the lethality of most of the new virus strains tended to remain the same or decreased, which had been suggested by several previous researches [6-8, 14, 15].…”