Impact of the Double Mutants on Spike Protein of SARS-CoV-2 B.1.617 Lineage on the Human ACE2 Receptor Binding: A Structural Insight

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.

Deciphering the Impact of Mutations on the Binding Efficacy of SARS-CoV-2 Omicron and Delta Variants With Human ACE2 Receptor

“…In addition, Y442, L472, N479, T487, L455, F486, and Q498 of RBD were observed to mediate hydrophobic interactions. Our finding was consistent with previous studies ( Antony and Vijayan, 2021 ; Khan M. I. et al, 2021 ; Celik et al, 2021 ; Kumar et al, 2021 ). However, some contradicting observations were also found.…”

Early introduction, dispersal and evolution of Delta SARS-CoV-2 in Southern Brazil, late predominance of AY.99.2 and AY.101 related lineages

“…Analyzing S-gene mutations in > 75% of sequences for lineages found in Brazil in the same period, the most common mutations mentioned are T19R, T95I, E156G, DEL157/158, L452R, T478K, D614G, Q677H, P681R, D950N, V1104L and L1265F ( Latif et al, 2021a ). Some of these mutations have been related to viral fitness advantages such as enhanced viral entry, infectivity, pathogenesis, and immune escape ( Khan et al, 2021 ; Korber et al, 2020 ; Li et al, 2020 ; Saito et al, 2021 ).…”

Molecular dynamics study on the strengthening behavior of Delta and Omicron SARS-CoV-2 spike RBD improved receptor-binding affinity

“…According to recent X-ray results [ 40 , 16 , 56 , 57 ], we found that the simulated structure of the ACE2-bound SARS-CoV-2 S-RBD protein preserves the same binding interface information, which does not induce any conformational change in the receptor-binding site [ 24 , 58 – 61 ]. One essential feature at the binding interface hotspot between S-RBD and ACE2 proteins is the number of hydrophilic residue interactions [ 16 , 40 ], which are conserved in the corresponding MD simulation calculation.…”

“…The side chain of the Q498R mutation forms two additional hydrogen bonds with Q42 and D38 from ACE2, and the N501Y mutation forms extensive packing interactions with the ACE2 residues Y41 and K353 [ 23 ]. Compared to Omicron, the Delta variant carries a characteristic L452R mutation, which is the strong binding interaction of the S-RBD protein described for ACE2 binding [ 24 ]; however, this mutation would not clash with the Y102 epitope from the heavy chain of the antibody, leading to its loss of potency against the Delta variant [ 25 ]. Both the Delta and Omicron variants share a common T478K exchange, while a low affinity for neutralizing antibodies at this position was observed for Delta [ 26 , 27 ].…”