The available crystal structure for the complex between the Fc fragment of immunoglobulin G (IgG) and the neonatal Fc receptor (FcRn) was determined at low resolution and has no electron density for a large portion of the CH2 domain of the Fc. Here, we use a well validated computational docking algorithm in conjunction with known crystallographic data to predict the orientation of CH2 when bound to FcRn, and validate the predicted structure with data from site-specific mutagenesis experiments. The predicted Fc structure indicates that the CH2 domain moves upon binding FcRn , such that the end-to-end distance of the bound Fc fragment is greater than it is in the crystal structure of isolated Fc. The calculated orientation of the bound CH2 domain is displaced by an average of 6 A from the CH2 orientation in the structure of Fc alone, and shows improved charge complementarity with FcRn. The predicted effects of 11 specific mutations in Fc and FcRn are calculated and the results are compared with experimental measurements. The predicted structure is consistent with all reported mutagenesis data, some of which are explicable only on the basis of our model. The current study predicts that FcRn-bound Fc is asymmetric due to reorientation of the CH2 domain upon FcRn binding, a rearrangement that would be likely to interfere with optimal binding of FcRn at the second binding site of the Fc homodimer.