Structural basis of fitness of emerging SARS-COV-2 variants and considerations for screening, testing and surveillance strategy to contain their threat

Abstract

While emergence of new SAS-COV-2 variants is posing grave challenge to efforts to deal with the COVID-19 pandemic, the structural and molecular basis of their fitness remain poorly understood. We performed in silico analysis of structures of two most frequent SARS-COV-2 mutations, namely, N501Y and E484K, to identify plausible basis of their fitness over the original strain. The analysis suggested that the N501Y mutation is associated with strengthening of intra- as well as intermolecular H-bond in the hACE2 receptor-spike protein complex, which could result in increased affinity and, therefore, higher infectivity. While E484K mutation did not seem to directly affect the binding with hACE2 receptor, it disrupted H-bonding and salt-bridge interaction associated with binding with neutralizing antibody, which could affect chance of re-infection, disease outcome. Survey of several other mutations showing reduction in antibody-mediated neutralization also revealed that similar disruption of H-bonding or salt-bridge or Van der Waals interaction might explain their phenotype. Analysis of GESS database indicated that N501Y, EK484 as well as these other mutations existed since March-April, 2020, might have evolved independently across the world and may keep accumulating, which could affect efficacy of vaccination and antibody-based therapies. Our analysis also indicated that these may spread in spite of current travel restrictions focused on few countries and evolve indigenously warranting intensification of surveillance for emerging mutations among all travellers as well as people in their dwelling zones. Meta-analysis of existing literature showed that repeat testing of travellers, contacts and others under scrutiny 7-11 days after the initial RT-PCR test may significantly help to contain the spread of emerging variants by catching false negative results. In addition, existing evidence calls for development of strain-specific tests, escalated sequencing and broadening the scope of surveillance including in hospitals and animal farms to contain the threat of emerging variants.

Molecular Insights into the Differential Dynamics of SARS-CoV-2 Variants of Concern (VOC)

“…Mutation E484K is known to contribute to the evasion of antibody neutralization [15]. D796H and H655Y mutations that are present in the Spike protein, are associated with reduced affinity towards the neutralizing antibodies [16]. The World Health Organization (WHO) has recently assigned different labels for the generated variants of SARS-CoV-2.…”

Emergence of SARS-CoV-2 New Variants and Their Clinical Significance

“…Different variations, such as UK (N501Y), South African (K417N-E484K-N501Y), Brazilian (K417T-E484K-N501Y), and hypothetical (K417T-E484K-N501Y), have varying binding affinity to receptors, according to structural and biophysical techniques (N501Y-E484K). Variants from South Africa (K417N-E484K-N501Y) and Brazil (K417T-E484K-N501Y) have shown to be more dangerous than the UK form (N501Y) [ 27 , 28 ].…”

“…The D614G mutant became the dominant virus over four months in China. The animal model and human respiratory cells studies show that this D614G mutation strain has a high infectivity and transmission rate compared with the normal strain [ 27 ].…”

“…Preliminary studies show that this virus neutralizes the normal strain and decreases the extent and duration of immunity developed by natural infection and vaccination. By September 2020, only 12 human cases had been identified in Denmark, and studies show that this variant is not spreading widely [ 27 , 32 ].…”

“…On 18th December 2020, the South African government announced the discovery of a new variety 501Y.V2 with the N501Y mutation [ 27 ]. The N501Y mutation is also seen in the SARS-CoV-2 VOC 202012/01 variant found in the UK, although evolutionary study reveals that these two variants are not related.…”