AbstractThe development of effective therapeutics against COVID‐19 requires a thorough understanding of the receptor recognition mechanism of the SARS‐CoV‐2 spike (S) protein. Here the multidomain collective dynamics on the trimer of the spike protein has been analyzed using normal mode analysis (NMA). A common nanomechanical profile was identified in the spike proteins of SARS‐CoV‐2 and its variants. The profile involves collective vibrations of the receptor‐binding domain (RBD) and the N‐terminal domain (NTD), which may mediate the physical interaction process. Quantitative analysis of the collective modes suggests a nanomechanical property involving large‐scale conformational changes, which explains the difference in receptor binding affinity among different variants. These results support the use of intrinsic global dynamics as a valuable perspective for studying the allosteric and functional mechanisms of the S protein. This approach also provides a low‐cost theoretical toolkit for screening potential pathogenic mutations and drug targets.