A theoretical approach to the functional changes in membrane proteins by phosphorylation

Although it has been experimentally demonstrated that functional changes in membrane proteins by phosphorylation play a crucial role in cellular signal transduction, a direct mechanism showing how negatively charged phosphates are involved in these phenomena has not yet been identified. To examine the origin of these functional changes, the structural and electric changes in intracellular phosphorylated loops were analyzed theoretically. Semi-empirical molecular orbital calculations showed that, when the intracellular loop is phosphorylated, (1) the negative charges of the phosphate are partly exuded into the loop; (2) the net charge distribution in the phosphorylated and its neighboring amino acid residues are changed; (3) the structure of the loop is also changed by the charge-transfer; and finally (4) the electric field around the loop is reformed. These results suggest that protein phosphorylation can influence not only the higher structure of the protein, but also its electric properties, thereby affecting such things as drug affinity and ionic permeability.