title: Insights into the mechanism of C5aR inhibition by PMX53 via implicit solvent molecular dynamics simulations and docking.
abstract: BACKGROUND
  The complement protein C5a acts by primarily binding and activating the G-protein coupled C5a receptor C5aR (CD88), and is implicated in many inflammatory diseases. The cyclic hexapeptide PMX53 (sequence Ace-Phe-[Orn-Pro-dCha-Trp-Arg]) is a full C5aR antagonist of nanomolar potency, and is widely used to study C5aR function in disease.
  
  
  RESULTS
  We construct for the first time molecular models for the C5aR:PMX53 complex without the a priori use of experimental constraints, via a computational framework of molecular dynamics (MD) simulations, docking, conformational clustering and free energy filtering. The models agree with experimental data, and are used to propose important intermolecular interactions contributing to binding, and to develop a hypothesis for the mechanism of PMX53 antagonism.
  
  
  CONCLUSIONS
  This work forms the basis for the design of improved C5aR antagonists, as well as for atomic-detail mechanistic studies of complement activation and function. Our computational framework can be widely used to develop GPCR-ligand structural models in membrane environments, peptidomimetics and other chemical compounds with potential clinical use.
authors.affiliation: Department of Physics, University of Cyprus, PO 20537, CY1678 Nicosia, Cyprus.
authors.forename: Phanourios
authors.initials: P
authors.lastname: Tamamis
authors.affiliation: Department of Bioengineering, University of California, Riverside, CA 92521, USA.
authors.forename: Chris A
authors.initials: CA
authors.lastname: Kieslich
authors.affiliation: MolLife Design LLC, St. Louis 63141, USA.
authors.forename: Gregory V
authors.initials: GV
authors.lastname: Nikiforovich
authors.affiliation: School of Biomedical Sciences, the University of Queensland, St Lucia 4072, Australia.
authors.forename: Trent M
authors.initials: TM
authors.lastname: Woodruff
authors.affiliation: Department of Bioengineering, University of California, Riverside, CA 92521, USA.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Morikis
authors.affiliation: Department of Physics, University of Cyprus, PO 20537, CY1678 Nicosia, Cyprus.
authors.forename: Georgios
authors.initials: G
authors.lastname: Archontis
keywords: C5a; C5aR; Class A GPCR; Complement system; Docking; Implicit solvent; Membrane protein; Molecular dynamics