Evaluating the potential role of ectodomain D3 in Fc-FcγRI complex via molecular dynamics simulations

FcγRI plays a significant role in the effector function of the IgGs. It interacts with the lower hinge region of IgG1-type antibodies with a nanomolar affinity. FcγRI characterization studies indicated that binding with IgGs occurs specifically in Domain 2 (D2) within the ectodomain of FcγRI. There is no report about direct function of Domain 3 in terms of binding event, but it is stated to be served as flexible linker at the cell surface. In this study, we have aimed to investigate more about the structural and functional properties of D3 domain within FcγRI via 200 ns classical MD simulations. Here, two models were constructed as (1) full model including FcγRI ectodomain complex with Fc, and (2) truncated model excluding D3 ectodomain in FcγRI ectodomain complex with Fc. Our findings have also suggested that D3 ectodomain is responsible to provide additional structural flexibility for FcγRI-Fc complex by not altering the Ca backbone motion and the flexibility of KHR binding motif in the FG loop. The critical residues involving in binding event and contributing the structural stability of FcγRI-Fc complex have been evaluated in terms of changes in intramolecular interactions together with the calculations of destabilization tendency to understand how these are affected without the presence of D3 ectodomain in FcγRI. Our MD simulations have suggested that there are no significant alterations in the required interactions around glycan interacted residues in Fc chains and FcγRI-Fc binding interfaces upon the truncation of D3 ectodomain in FcγRI. By limiting the mobility of FcγRI-Fc complex with the truncation of D3 ectodomain, the more promising biotechnological applications would be possible for further utilization of FcγRI-Fc complex.