Abstract
Simple SummaryThe current study provides an insight into the binding and dynamic differences between wild-type RBD and B.1.620, which harbor S477N-E484K mutations in the spike protein’s receptor-binding domain (RBD). Our analysis revealed that though the number of hydrogen bonds and salt bridges remained the same, the binding affinity of B.1.620 for ACE2 was higher than that of the wild type, consequently increasing infectivity. Moreover, the stable dynamics and other features further justify the findings, corroborating the previous literature. Recently, a new variant, B.1620, with mutations (S477N-E484K) in the spike protein’s receptor-binding domain (RBD) has been reported in Europe. In order to design therapeutic strategies suitable for B.1.620, further studies are required. A detailed investigation of the structural features and variations caused by these substitutions, that is, a molecular level investigation, is essential to uncover the role of these changes. To determine whether and how the binding affinity of ACE2–RBD is affected, we used protein–protein docking and all-atom simulation approaches. Our analysis revealed that B.1.620 binds more strongly than the wild type and alters the hydrogen bonding network. The docking score for the wild type was reported to be −122.6 +/− 0.7 kcal/mol, while for B.1.620, the docking score was −124.9 +/− 3.8 kcal/mol. A comparative binding investigation showed that the wild-type complex has 11 hydrogen bonds and one salt bridge, while the B.1.620 complex has 14 hydrogen bonds and one salt bridge, among which most of the interactions are preserved between the wild type and B.1.620. A dynamic analysis of the two complexes revealed stable dynamics, which corroborated the global stability trend, compactness, and flexibility of the three essential loops, providing a better conformational optimization opportunity and binding. Furthermore, binding free energy revealed that the wild type had a total binding energy of −51.14 kcal/mol, while for B.1.628, the total binding energy was −68.25 kcal/mol. The current findings based on protein complex modeling and bio-simulation methods revealed the atomic features of the B.1.620 variant harboring S477N and E484K mutations in the RBD and the basis for infectivity. In conclusion, the current study presents distinguishing features of B.1.620, which can be used to design structure-based drugs against the B.1.620 variant.
Highlights
As coronaviruses continue to emerge at numerous intervals and spread at staggering levels around the world, they fall into four genera, namely, α, β, γ, and δ, in the Orthocoronavirinae subfamily of the family Coronaviridae [1,2,3]
To explore the role of these mutations and the impact on the binding of receptor-binding domain (RBD) with ACE2, we employed molecular docking, hydrogen bonding network, and molecular dynamics simulation analyses to explore the variations in affinity and binding in comparison with the wild type
The structure of the spike RBD in the complex with ACE2 was retrieved from RCSB, and mutations were introduced into the sequence
Summary
As coronaviruses continue to emerge at numerous intervals and spread at staggering levels around the world, they fall into four genera, namely, α, β, γ, and δ, in the Orthocoronavirinae subfamily of the family Coronaviridae [1,2,3]. The rapid spread of SARS-CoV-2 and the appearance of novel variants pose an increased risk to human health. Variations in different proteins of SARS-CoV-2, the spike glycoprotein, lead to a drift in the antigenicity of vaccines or other therapeutics [12,13,14,15]. Due to the phenomenal spread of VOCs, they remained a concern because of their enhanced transmission, causing more severe disease, a significant decline in antibody neutralization, and decreased treatment effectiveness [17]. The substitution of D614 for G614 in the spike glycoprotein causes changes in the conformation of the cleavage site loop, leading to more effective S1 and S2 cleavage by enhancing furin accessibility [18]. Most SARS-CoV-2 isolates have the D614G mutation [19]
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