Possible link between higher transmissibility of B.1.617 and B.1.1.7 variants of SARS-CoV-2 and increased structural stability of its spike protein and hACE2 affinity

Abstract

The Severe Acute syndrome corona Virus 2 (SARS-CoV-2) outbreak in December 2019 has caused a global pandemic. The rapid mutation rate in the virus has caused alarming situations worldwide and is being attributed to the false negativity in RT-PCR tests, which also might lead to the inefficacy of the available drugs. It has also increased the chances of reinfection and immune escape. We have performed Molecular Dynamic simulations of three different Spike-ACE2 complexes, namely Wildtype (WT), B.1.1.7 variant (N501Y Spike mutant) and B.1.617 variant (L452R, E484Q Spike mutant) and compared their dynamics, binding energy and molecular interactions. Our result shows that mutation has caused the increase in the binding energy between the Spike and hACE2. In the case of B.1.617 variant, the mutations at L452R and E484Q increased the stability and intra-chain interactions in the Spike protein, which may change the interaction ability of human antibodies to this Spike variant. Further, we found that the B.1.1.7 variant had increased hydrogen interaction with LYS353 of hACE2 and more binding affinity in comparison to WT. The current study provides the biophysical basis for understanding the molecular mechanism and rationale behind the increase in the transmissivity and infectivity of the mutants compared to wild-type SARS-CoV-2.

Structure-guided T cell vaccine design for SARS-CoV-2 variants and sarbecoviruses

“…An effective vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a major global health priority. While multiple vaccine candidates have been developed using a variety of platforms to deliver the viral spike protein and induce neutralizing antibodies (Baden et al, 2021;Folegatti et al, 2020;Keech et al, 2020;Polack et al, 2020;Sadoff et al, 2021), the emergence of the B.1.1.7 alpha (Tang et al, 2020), B.1.351 beta (Tegally et al, 2021), P.1 gamma (Voloch et al, 2020), and B.1.617.2 delta variants (Cherian et al, 2021) has raised substantial new concerns due to their increased transmissibility (Davies et al, 2021;Kumar et al, 2021) and ability to escape convalescent and vaccine-induced antibody responses (Garcia-Beltran et al, 2021;Hoffmann et al, 2021;Madhi et al, 2021;Wang et al, 2021;Wibmer et al, 2021). In addition, given that SARS-CoV-2 is the third coronavirus outbreak in the past 20 years (after SARS-CoV-1 and Middle East respiratory syndrome coronavirus [MERS-CoV]), significant additional concerns exist about a future pandemic due to the numerous SARS-like coronaviruses identified in the bat reservoir (Menachery et al, 2015(Menachery et al, , 2016.…”

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

“…The mutation-induced conformational changes in these new reported variants might also make the vaccines or neutralizing antibodies (nAbs) ineffective [21,22,26,27]. The recently reported SARS-CoV-2 variant B.1.617 (delta and kappa) are responsible for the steep rise in the number of COVID-19 cases and deaths in India [28][29][30]. The emergence of these new SARS-CoV-2 variants is believed to be highly responsible for several million new infections, leading to thousands of new deaths within a few weeks [29].…”

Original Hosts, Clinical Features, Transmission Routes, and Vaccine Development for Coronavirus Disease (COVID-19)

“…Compared with wild type, E484Q and L452R mutants in B.1.617 lineage demonstrated an increased hydrogen bond interaction with hACE2. In addition, B.1.617 mediated an enhanced entry into the human lung and intestine-derived cell lines Calu-3 and Caco-2, respectively, suggesting a higher transmissibility (165,166). Compared with B.1 (D614G) variant, the increased severity of B.1.617 infection in hamsters was evident by the higher viral load and body weight reduction, and more sever lung lesions (167).…”