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It decorates the virus surface and undergoes large motions of its receptor binding domains (RBDs) to enter the host cell. Here, we observe Down, one-Up, one-Open, and two-Up-like structures in enhanced molecular dynamics simulations, and characterize the transition pathways via inter-domain interactions. Transient salt-bridges between RBD\n                    <jats:sub>A<\/jats:sub>\n                    and RBD\n                    <jats:sub>C<\/jats:sub>\n                    and the interaction with glycan at N343\n                    <jats:sub>B<\/jats:sub>\n                    support RBD\n                    <jats:sub>A<\/jats:sub>\n                    motions from Down to one-Up. Reduced interactions between RBD\n                    <jats:sub>A<\/jats:sub>\n                    and RBD\n                    <jats:sub>B<\/jats:sub>\n                    in one-Up induce RBD\n                    <jats:sub>B<\/jats:sub>\n                    motions toward two-Up. The simulations overall agree with cryo-electron microscopy structure distributions and FRET experiments and provide hidden functional structures, namely, intermediates along Down-to-one-Up transition with druggable cryptic pockets as well as one-Open with a maximum exposed RBD. The inherent flexibility of S-protein thus provides essential information for antiviral drug rational design or vaccine development.\n                  <\/jats:p>","DOI":"10.7554\/elife.75720","type":"journal-article","created":{"date-parts":[[2022,3,16]],"date-time":"2022-03-16T14:15:18Z","timestamp":1647440118000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.75720","source":"Crossref","is-referenced-by-count":77,"title":["The inherent flexibility of receptor binding domains in SARS-CoV-2 spike protein"],"prefix":"10.7554","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4387-4790","authenticated-orcid":true,"given":"Hisham M","family":"Dokainish","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01sjwvz98","id-type":"ROR","asserted-by":"publisher"}],"name":"Theoretical Molecular Science Laboratory, RIKEN Cluster for Pioneering Research","place":["Wako, 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