Immunoglobulin G1 Fc Domain Motions: Implications for Fc Engineering

The fragment crystallizable (Fc) region links the key pathogen identification and destruction properties of immunoglobulin G (IgG). Pathogen opsonization positions Fcs to activate pro-inflammatory Fc gamma receptors (Fc gamma Rs) on immune cells. The cellular response and committal to a damaging, though protective, immune response are tightly controlled at multiple levels. Control mechanisms are diverse and in many cases unclear, but one frequently suggested contribution originates in Fc gamma R affinity being modulated through shifts in Fc conformational sampling. Here, we report a previously unseen IgG1 Fc conformation. This observation motivated an extensive molecular dynamics investigation of polypeptide and glycan motions that revealed greater amplitude of motion for the N-terminal C gamma 2 domains and N-glycan than previously observed. Residues in the C gamma 2/C gamma 3 interface and disulfide-bonded hinge were identified as influencing the C gamma 2 motion. Our results are consistent with a model of Fc that is structurally dynamic. Conformational states that are competent to bind immune-stimulating Fc gamma Rs interconverted with Fc conformations distinct from those observed in Fc gamma R complexes, which may represent a transient, nonbinding population. (C) 2014 Elsevier Ltd. All rights reserved.