Insights into the mechanism of C5aR inhibition by PMX53 via implicit solvent molecular dynamics simulations and docking.

Authors:
Phanourios Tamamis
Phanourios Tamamis
University of Cyprus
Chris A Kieslich
Chris A Kieslich
University of California
United States
Gregory V Nikiforovich
Gregory V Nikiforovich
Washington University Medical School
United States
Trent M Woodruff
Trent M Woodruff
School of Biomedical Sciences
Orlando | United States
Dimitrios Morikis
Dimitrios Morikis
University of California
Georgios Archontis
Georgios Archontis
University of Cyprus

BMC Biophys 2014 12;7. Epub 2014 Aug 12.

Department of Physics, University of Cyprus, PO 20537, CY1678 Nicosia, Cyprus.

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.

Conclusion: 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.

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http://dx.doi.org/10.1186/2046-1682-7-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4141665PMC
August 2014
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