However, the energy contribution of R501 in Omicron variant is greatly larger than N501 in WT. Therefore, the combined effects of the above mutations make the final binding free energy change subtle. Nevertheless, from the change in energy contributions of mutations between WT and Delta variant, there are not huge differences in those four mutations (residue 452, 478, 417, 484). From overall per residue energy decomposition results in the receptor-binding motif (RBM) region (Figure ), the binding free energies of F486, Y489, F490 increase in Delta mutant compared with WT. This implies that these residues in Delta variant may contribute more to hydrophobic effects and thus the final affinity to ACE2 is improved. (B) Energy contributions of RBM residues (437-507).