According to our prediction, the percentage of relative binding free energy between wild type NTD and R246I mutant to antibodies are -28.85%, -16.95%, -13.87% and -13.72% for 1-87 (PDB ID:7L2D), 2-51 (PDB ID: 7L2C), S2M28 (PDB ID: 7LY2) and S2L28 (PDB ID:7LXZ) respectively, implying R246I mutation is possible to impair the efficacies of these four antibodies (Figure , Table ). One of the most noteworthy things is that the affinity decreases the most for antibody 1-87 (PDB ID: 7L2D). These results suggest that it is best to avoid using these four types of antibodies alone, especially 1-87, against variants with R246I mutations. Moreover, the ΔΔG for 4-18 (PDB ID:7L2E), DH1052 (PDB ID:7LAB) and S2X333 (PDB ID:7LXY) are around 0 kcal/mol (Table ), which is indicative of negligible impact on binding affinity (P value > 0.01). These three antibodies may not be susceptible to R246I mutation, so when targeting a mutant strain of SARS-COV-2 that has R246I mutation, they may work even better. Our findings can provide guidance on the clinical use of NTD antibodies. The binding free energy in WT is filled with blue, and the binding free energy in R246I mutant is filled with dark red. The relative binding free energy percentage (ΔΔG/ΔGWT =(ΔGR246I-ΔGWT)/ ΔGWT) between WT and R246I is filled with cyan. 251 snapshots from 30-60ns trajectories are used for per residue energy decomposition.