SARS-CoV-2 spike protein is continuously accumulating mutations, leading to the emergence of new variants and a corresponding increase in the number of infected cases. Our published results on its receptor binding domain (RBD) showed that increased receptor binding and escape from neutralizing antibodies direct the natural selection of RBD mutations. However, mutations have also been identified in other regions of the spike protein that are distant from the RBD, and the role of these non-RBD mutations remains unclear. The spike protein is a trimer, with each of its RBDs either in the up conformation, which is available for binding to the human ACE2 receptor, or in the down conformation, which is inaccessible to the ACE2 receptor. Using conventional double mutant cycles and techniques such as SPR and cryo-EM, we demonstrate here that these non-RBD mutations significantly increase the RBD-up conformational states, indicating a long-range allosteric conformation in the spike protein.
Lucas et al. (Sun,) studied this question.