Abstract
The recent emergence of novel SARS-CoV-2 variants has threatened the efforts to contain the COVID-19 pandemic. The emergence of these “variants of concern” has increased immune escape and has supplanted the ancestral strains. The novel variants harbored by the B.1.617 lineage (kappa and delta) carry mutations within the receptor-binding domain of spike (S) protein (L452R + E484Q and L452R + T478K), the region binding to the host receptor. The double mutations carried by these novel variants are primarily responsible for an upsurge number of COVID-19 cases in India. In this study, we thoroughly investigated the impact of these double mutations on the binding capability to the human host receptor. We performed several structural analyses and found that the studied double mutations increase the binding affinity of the spike protein to the human host receptor (ACE2). Furthermore, our study showed that these double mutants might be a dominant contributor enhancing the receptor-binding affinity of SARS-CoV-2 and consequently making it more stable. We also investigated the impact of these mutations on the binding affinity of two monoclonal antibodies (Abs) (2-15 and LY-CoV555) and found that the presence of the double mutations also hinders its binding with the studied Abs. The principal component analysis, free energy landscape, intermolecular interaction, and other investigations provided a deeper structural insight to better understand the molecular mechanism responsible for increased viral transmissibility of these variants.
Highlights
Today, the entire world is struggling with coronavirus disease 2019 (COVID-19), a pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1]
The reference complex structures along with the kappa (L452R, E484Q) and delta variant (L452R and T478K) models were subjected to two hundred nanoseconds of MD simulations
The kappa variant witnessed the lowest level of fluctuations within the amino acid residues, suggesting the better stability of the kappa variant complex followed by the delta variant
Summary
The entire world is struggling with coronavirus disease 2019 (COVID-19), a pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1]. This virus has rapidly spread worldwide, and subsequently, its infectivity has been reported from every part of the world [2,3,4]. One of the main attributes of viruses is their ability to mutate frequently [5,6]. The occurrence of new mutations affects the virulence and transmission of the virus [7,8,9]. The Spike (S) protein is an essential part of SARS-CoV-2 as it mediates interaction with the human cells and is the target for most vaccine and therapeutic antibodies (Abs) [10,11]
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