Molecular Modeling Study On The Recognition Mechanism Of CR2and C3D

The complement system acts as an important linker between innate and adaptive immunity. The association of the complement component C3d, a degradation product of the complement C3, and complement receptor2can affect the antibody-mediated adative immunity. To explore the mechanism of C3d-CR2(SCRl-2) recognition and thus obtain key information for vaccine design, we explored the influence of the ion strengths (0,50,100and150mmol/L), pH (7.4,6.0and5.0) and the oligosaccharide attached to Asn107of SCR2of CR2on C3d-CR2interactions by molecular dynamics simulations and binding free energy calculations.At the ion sthength of0mmol/L, for C3d, residue energy decomposition analysis shows that the identified hotspot residues are Ala101, Asn98, Pro294, Ile100, Lys251, Asp103, Va197, Ile102, Glu39, Asp36, Aspl63and Ile164. The largest continuous areas on C3d is from Va197to Gln105. For CR2(SCRl-2), the identified hotspot residues are Tyr16, Arg28, Va126, Arg13, Arg89, Ser15, Thr25, Pro87, Gly24, Arg36and Lys67. When increasing the ion sthength from50mmol/L to150mmol/L or reducing pH from7.4to5.0, the binding affinity of C3d. and CR2(SCRl-2) is gradually weaken. The origin of the changes of the binding affinity is primarily from the reduced intermolecular van der Waals interaction energy and polar interaction energy. The energy contributions of Va197, Lys291and Asp292of C3d and Arg28, Arg89and Arg36of CR2(SCR1-2) are closely related to the ion sthength. The energy contributions of Glu39, Lys291, Asp292and Pro294of C3d and Arg13, Arg28, Arg36and Arg89of CR2(SCRl-2) depend on pH largely. Compared with the system unbound to oligosaccharide, oligosaccharide is favorable to the association of C3d with CR2(SCR1-2). Oligosaccharide can increase the energy contributions of Lys251, Glnl68and Va197of C3d and that of Arg13of CR2(SCRl-2).The analysis of interdomain angles indicates that CR2(SCRl-2) associated with C3d can reduce interdomain mobility and is favorable to open the V-shape conformation of CR2(SCR1-2). The increased ion sthength or the decreased pH or a natural branched oligosaccharide can reduce interdomain mobility and have minor influence on the V-shape conformation of CR2(SCR1-2). The principal component analysis and cluster analysis indicate mat the linker of CR2(SCR1-2) mediates interactions of C3d and CR2(SCRl-2) and interdomain interactions through Try68. The analysis of correlation and water density indicates that the antigen binding site can mediates the interactions of C3d and CR2(SCR1-2) through water.The results in this paper indicate that interactions of C3d and CR2(SCRl-2) depend on pH and ion strengths and that the oligosaccharide has an effect on interactions of C3d and CR2(SCR1-2). The origin of the effects of pH, ion sthength and oligosaccharide is their effects on the hydration sites located around the antigen binding site. This valuable information obtained in the study can provide theoretical guidance in vaccine design and in design of inhibitors in autoimmune circumstances.