Article

Cellular and Molecular Bioengineering

, Volume 5, Issue 1, pp 32-43

Complement Inhibition by Staphylococcus aureus: Electrostatics of C3d–EfbC and C3d–Ehp Association

  • Ronald D. GorhamJr.Affiliated withDepartment of Bioengineering, University of California at Riverside
  • , Chris A. KieslichAffiliated withDepartment of Bioengineering, University of California at Riverside
  • , Dimitrios MorikisAffiliated withDepartment of Bioengineering, University of California at Riverside Email author 

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Abstract

Virulence factors EfbC and Ehp from Staphylococcus aureus are potent inhibitors of complement activation. Both are excessively charged and bind to complement protein C3d at an acidic interface. We computationally generated single-alanine mutants of charged residues in the C3d–EfbC and C3d–Ehp complexes, and utilized electrostatic clustering and Poisson–Boltzmann free energy calculations to evaluate the role of electrostatics in association. Our results indicate that both interfacial electrostatic interactions and electrostatic potential distribution are crucial for C3d–EfbC and C3d–Ehp association. The results presented herein serve as a predictive tool in the selection of mutants with desired binding and immunological activity, and will narrow the search for viable candidates for further computational and experimental analyses. This study serves as the foundation for development of an inhibitor of the C3d–EfbC and C3d–Ehp interactions to combat bacterial infection and design of a complement inhibitor using EfbC and Ehp as a model.

Keywords

C3 Bacterial infection Poisson–Boltzmann electrostatics Electrostatic clustering Electrostatic free energy Alanine scan