Probing the Increased Virulence of Severe Acute Respiratory Syndrome Coronavirus 2 B.1.617 (Indian Variant) From Predicted Spike Protein Structure.

Houssein Hajj-Hassan,Hassan M Khachfe,Kassem Hamze,Nadeem Kizilbash,Fadi Abdel Sater

doi:10.7759/cureus.16905

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to an outbreak of a pandemic worldwide. The spike (S) protein of SARS-CoV-2, which plays a key role in the receptor recognition and cell membrane fusion process, is composed of two subunits, S1 and S2. The S1 subunit contains a receptor-binding domain that recognizes and binds to the host receptor angiotensin-converting enzyme 2 (ACE2), while the S2 subunit mediates viral cell membrane fusion with the cell membrane and subsequent entry into cells. Mutations in the spike protein (S) are of particular interest due to their potential for reduced susceptibility to neutralizing antibodies or increasing the viral transmissibility and infectivity. Recently, many mutations in the spike protein released new variants, including the Delta and Kappa ones (known as the Indian variants). The variants Delta and Kappa are now of most recent concern because of their well-increased infectivity, both a spin-off of the B.1.617 lineage, which was first identified in India in October 2020. This study employed homology modeling to probe the potential structural effects of the mutations. It was found that the mutations, Leu452Arg, Thr478Lys, and Glu484Gln in the spike protein increase the affinity for the hACE2 receptor, which explains the greater infectivity of the SARS-Cov-2 B.1.617 (Indian Variant).

Highlights

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the COVID-19 pandemic, which, for more than one year, has been associated with a record number of cases and deaths [1]
We have focused on the Delta and Kappa variants and utilized homology modeling (HM) simulations of S protein trimer to assess its dynamic behavior in terms of conformational stability as well as the interaction of isolated viral receptor-binding domain (RBD) in complex with human angiotensin-converting enzyme 2 (ACE2) to probe the specific interactions emanating from the double mutations (L452R/E484Q in Kappa and L452R/T478K in Delta) in the RBD-ACE2 complexes
It has been suggested that children have ACE2 receptors with a lower affinity for SARS-CoV-2 and a different distribution across body sites, making the entry of SARS-CoV-2 into cells more difficult [28]

Summary

Introduction

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the COVID-19 pandemic, which, for more than one year, has been associated with a record number of cases and deaths [1]. Numerous strategies to fight this pandemic by vaccines or non-pharmaceutical interventions (e.g., forced lock-downs, masking up, hand washing, social distancing, etc.) have been lagged by the emergence of SARS-CoV-2 variants of concern (VOC). These variants harbor mutations that confer increased transmissibility (and death cases as a consequence) or immune evasion [2]. The spike protein is 1,273 amino acids long with two important functional regions: the N-terminal region (S1) (amino acids (aa) 14-682) responsible for viral attachment to target cells via the angiotensin-converting enzyme 2 (ACE2) receptor, and the C-terminal region (S2) (aa 686-1273) responsible for membrane fusion and cell entry [8]. S1 is cleaved from S2 in the cleavage region (aa 682- 685)

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