Proteins　usually　undergo　conformational　transitions　between　structurally　disparate　states　to　fulfill　their　functions.　The　large-scale　allosteric　conformational　transitions　are　believed　to　involve　some　key　residues　that　mediate　the　conformational　movements　between　different　regions　of　the　protein.　In　the　present　work,　a　thermodynamic　method　based　on　the　elastic　network　model　is　proposed　to　predict　the　key　residues　involved　in　protein　conformational　transitions.　In　our　method,　the　key　functional　sites　are　identified　as　the　residues　whose　perturbations　largely　influence　the　free　energy　difference　between　the　protein　states　before　and　after　transition.　Two　proteins,　nucleotide　binding　domain　of　the　heat　shock　protein　70　and　human/rat　DNA　polymerase　beta,　are　used　as　case　studies　to　identify　the　critical　residues　responsible　for　their　open-closed　conformational　transitions.　The　results　show　that　the　functionally　important　residues　mainly　locate　at　the　following　regions　for　these　two　proteins:　(1)　the　bridging　point　at　the　interface　between　the　subdomains　that　control　the　opening　and　closure　of　the　binding　cleft;　(2)　the　hinge　region　between　different　subdomains,　which　mediates　the　cooperative　motions　between　the　corresponding　subdomains;　and　(3)　the　substrate　binding　sites.　The　similarity　in　the　positions　of　the　key　residues　for　these　two　proteins　may　indicate　a　common　mechanism　in　their　conformational　transitions.　(C)　2011　American　Institute　of　Physics.　[doi:10.1063/1.3651480]