title: Molecular analysis of the interaction between staphylococcal virulence factor Sbi-IV and complement C3d.
abstract: Staphylococcus aureus expresses numerous virulence factors that aid in immune evasion. The four-domain staphylococcal immunoglobulin binding (Sbi) protein interacts with complement component 3 (C3) and its thioester domain (C3d)-containing fragments. Recent structural data suggested two possible modes of binding of Sbi domain IV (Sbi-IV) to C3d, but the physiological binding mode remains unclear. We used a computational approach to provide insight into the C3d-Sbi-IV interaction. Molecular dynamics (MD) simulations showed that the first binding mode (PDB code 2WY8) is more robust than the second (PDB code 2WY7), with more persistent polar and nonpolar interactions, as well as conserved interfacial solvent accessible surface area. Brownian dynamics and steered MD simulations revealed that the first binding mode has faster association kinetics and maintains more stable intermolecular interactions compared to the second binding mode. In light of available experimental and structural data, our data confirm that the first binding mode represents Sbi-IV interaction with C3d (and C3) in a physiological context. Although the second binding mode is inherently less stable, we suggest a possible physiological role. Both binding sites may serve as a template for structure-based design of novel complement therapeutics.
authors.affiliation: Department of Bioengineering, University of California, Riverside, California.
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Gorham
authors.affiliation: Department of Bioengineering, University of California, Riverside, California.
authors.forename: Wilson
authors.initials: W
authors.lastname: Rodriguez
authors.affiliation: Department of Bioengineering, University of California, Riverside, California. Electronic address: dmorikis@ucr.edu.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Morikis
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D015933:Complement C3d / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D055550:Protein Stability; D055672:Static Electricity; D037521:Virulence Factors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D002352:Carrier Proteins; C112405:Sbi protein, Staphylococcus aureus; D037521:Virulence Factors; D015933:Complement C3d