Impact of E484Q and L452R Mutations on Structure and Binding Behavior of SARS-CoV-2 B.1.617.1 Using Deep Learning AlphaFold2, Molecular Docking and Dynamics Simulation

During the outbreak of COVID-19, many SARS-CoV-2 variants presented key amino acid mutations that influenced their binding abilities with angiotensin-converting enzyme 2 (hACE2) and neutralizing antibodies. For the B.1.617 lineage, there had been fears that two key mutations, i.e., L452R and E484Q, would have additive effects on the evasion of neutralizing antibodies. In this paper, we systematically investigated the impact of the L452R and E484Q mutations on the structure and binding behavior of B.1.617.1 using deep learning AlphaFold2, molecular docking and dynamics simulation. We firstly predicted and verified the structure of the S protein containing L452R and E484Q mutations via the AlphaFold2-calculated pLDDT value and compared it with the experimental structure. Next, a molecular simulation was performed to reveal the structural and interaction stabilities of the S protein of the double mutant variant with hACE2. We found that the double mutations, L452R and E484Q, could lead to a decrease in hydrogen bonds and higher interaction energy between the S protein and hACE2, demonstrating the lower structural stability and the worse binding affinity in the long dynamic evolutional process, even though the molecular docking showed the lower binding energy score of the S1 RBD of the double mutant variant with hACE2 than that of the wild type (WT) with hACE2. In addition, docking to three approved neutralizing monoclonal antibodies (mAbs) showed a reduced binding affinity of the double mutant variant, suggesting a lower neutralization ability of the mAbs against the double mutant variant. Our study helps lay the foundation for further SARS-CoV-2 studies and provides bioinformatics and computational insights into how the double mutations lead to immune evasion, which could offer guidance for subsequent biomedical studies.