ABSTRACT
The pandemic caused by SARS-CoV-2 has cost millions of lives and tremendous social/financial loss. The virus continues to evolve and mutate. In particular, the recently emerged "UK", "South Africa", and Delta variants show higher infectivity and spreading speed. Thus, the relationship between the mutations of certain amino acids and the spreading speed of the virus is a problem of great importance. In this respect, understanding the mutational mechanism is crucial for surveillance and prediction of future mutations as well as antibody/vaccine development. In this work, we used a coarse-grained model (that was used previously in predicting the importance of mutations of N501) to calculate the free energy change of various types of single-site or combined-site mutations. This was done for the UK, South Africa, and Delta mutants. We investigated the underlying mechanisms of the binding affinity changes for mutations at different spike protein domains of SARS-CoV-2 and provided the energy basis for the resistance of the E484 mutant to the antibody m396. Other potential mutation sites were also predicted. Furthermore, the in silico predictions were assessed by functional experiments. The results establish that the faster spreading of recently observed mutants is strongly correlated with the binding-affinity enhancement between virus and human receptor as well as with the reduction of the binding to the m396 antibody. Significantly, the current approach offers a way to predict new variants and to assess the effectiveness of different antibodies toward such variants.