Structure-Based Modeling of Complement C4 Mediated Neutralization of Adenovirus

Area of Science:

• Virology
• Immunology
• Structural Biology

Background:

• Adenovirus (AdV) infection triggers immune responses, including neutralizing antibodies and complement activation.
• The anti-hexon antibody 9C12 activates complement, leading to C4b deposition and AdV neutralization.
• C4b-mediated neutralization blocks protein VI release, essential for viral endosomal escape.

Purpose of the Study:

• To investigate the structural mechanisms by which C4b blocks AdV uncoating.
• To model the complex of human adenovirus type-5 (HAdV5) with 9C12, C1, and C4b.

Main Methods:

• Computational modeling of the HAdV5-9C12-C1-C4b complex.
• Molecular dynamics simulations of penton base multimers with C4b.

Main Results:

• The model positions C4b near the Arg-Gly-Asp (RGD) loops of the penton base.
• C4b potentially binds covalently to amino acids within the RGD loops.
• Simulations suggest stabilizing interactions between C4b and multiple RGD loops.

Conclusions:

• C4b deposition on one RGD loop may entangle with other RGD loops on the same penton base multimer.
• This entanglement mechanism is proposed to physically block AdV uncoating.
• Understanding this interaction provides structural insights into complement-mediated viral neutralization.