Global conformational flexibility versus local accessibility of phosphosite and conformational trapping by inhibitors. A) Protein flexibility or conformational changes were computed from the molecular weight of the proteins and compared with the experimentally determined SASA values for proteins from phosphosite data falling under disallowed (<0.2) and allowed region of phosphoconformation (>0.2). Arel was calculated as the ratio of experimentally determined SASA to the predicted SASA. Dark bars indicate proteins in disallowed region of phosphoconformation while the light bars indicate those in the allowed region of conformation. B) The concept of conformational trapping by kinases vis a vis inhibitors is depicted using the free energy landscape. Protein in which the phosphosite is inaccessible is imagined to be in a low energy stable state (1) and the same site however may become accessible in a similar (2) or a high energy state (3). These conformations can be trapped by a kinase leading to phosphorylation (4) which stabilizes the protein and lowers its free energy. The phosphorylated ‘active’ state of the protein is shown here at a higher energy level (5) than the conformation in which the phosphosite is inaccessible. Action of a phosphatase may relieve the excess energy. C) This cartoon depicts conformational trapping by inhibitors. An inhibitor can bind to an allosteric site in the disallowed region of phosphoconformation freezing the protein in this kinase inaccessible state. Other inhibitors may bind to similar or higher energy conformations in which the phosphosite is increasingly accessible howoever inhibitor binding induces conformational changes rendering the phsophosite inaccessible to a kinase. The kinase accessible site may also be trapped by inhibitors competing at the phosphosite (not shown).