title: Species specificity of the complement inhibitor compstatin investigated by all-atom molecular dynamics simulations.
abstract: The development of compounds to regulate the activation of the complement system in non-primate species is of profound interest because it can provide models for human diseases. The peptide compstatin inhibits protein C3 in primate mammals and is a potential therapeutic agent against unregulated activation of complement in humans but is inactive against nonprimate species. Here, we elucidate this species specificity of compstatin by molecular dynamics simulations of complexes between the most potent natural compstatin analog and human or rat C3. The results are compared against an experimental conformation of the human complex, determined recently by X-ray diffraction at 2.4-A resolution. The human complex simulations provide information on the relative contributions to stability of specific C3 and compstatin residues. In the rat simulations, the protein undergoes reproducible conformational changes, which eliminate or weaken specific interactions and reduce the complex stability. The simulation insights can be used to design improved compstatin-based inhibitors for human C3 and active inhibitors against lower mammals.
authors.affiliation: Department of Physics, University of Cyprus, PO20537, Nicosia CY1678, Cyprus.
authors.forename: Phanourios
authors.initials: P
authors.lastname: Tamamis
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Morikis
authors.forename: Christodoulos A
authors.initials: CA
authors.lastname: Floudas
authors.forename: Georgios
authors.initials: G
authors.lastname: Archontis
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003176:Complement C3 / Q000737:chemistry* / Q000378:metabolism; D003169:Complement Inactivator Proteins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D051381:Rats; D016415:Sequence Alignment; D013045:Species Specificity; D014961:X-Ray Diffraction
chemical_list: D003176:Complement C3; D003169:Complement Inactivator Proteins; D010456:Peptides, Cyclic; C111828:compstatin