The molecular mechanism of pH-regulating C3d-CR2 interactions: Insights from molecular dynamics simulation

The interactions of complement receptor 2 (CR2) and the degradation fragment C3d of complement component C3 mediate the innate and adaptive immune systems. Due to the importance of C3d-CR2 interaction in the design of vaccines, many studies have indicated the interactions are pH-dependent. Moreover, C3d-CR2 interactions at pH 5.0 are unknown. To investigate the molecular mechanism of pH-regulating C3d-CR2 interaction, molecular dynamics simulations for C3d-CR2 complex in different pH are performed. Our results revealed that the protonation of His9 in C3d at pH 6.0 slightly weakens C3d-CR2 association as reducing pH from 7.4 to 6.0, initiated from a key hydrogen bond formed between Gly270 and His9 in C3d at pH 6.0. When reducing pH from 6.0 to 5.0, the protonation of His33 in C3d weakens C3d-SCR1 association by changing the hydrogen-bond network of Asp36, Glu37, and Glu39 in C3d with Arg13 in CR2. In addition, the protonation of His90 significantly enhances C3d-SCR2 association. This is because the enhanced hydrogen-bond interactions of His90 with Glu63 and Ser69 of the linker change the conformations of the linker, Cys112-Asn116 and Pro87-Gly91 regions. This study uncovers the molecular mechanism of the mediation of pH on C3d-CR2 interaction, which is valuable for vaccine design.