The molecular mechanism of pH regulating C3d‐CR2 interactions: insights from molecular dynamics simulation

At pH5.0, the protonation of His90 in CR2 leads to the formation of a stable hydrogen bond with Glu63 and His90 and weakening the hydrogen‐bond interactions between His90 and Cys112. As a result, the interactions between Pro87‐Gly91 and Glu63‐Ser69 regions are enhanced and between Cys112‐Asn116 and Pro87‐Gly91 regions are weakend, which enhances the interaction between C‐terminal SCR2 and C3d.

Abstract

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 pH5.0 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 pH6.0 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 pH6.0. 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 and further changes 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.

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