The Model Structures of the Complement Component 5a Receptor (C5aR) Bound to the Native and Engineered ^hC5a

Area of Science:

• Structural Biology and Pharmacology
• Molecular Dynamics Simulations
• Biochemistry

Background:

• The interaction between human complement factor 5a (hC5a) and its receptor (C5aR) is crucial in inflammatory responses.
• Previous hypotheses suggested a "two-site" binding model for hC5a-C5aR, involving the N-terminus (NT) and extracellular surface (ECS) of C5aR.
• The precise atomistic details and pharmacological implications of these binding sites remained unclear.

Purpose of the Study:

• To provide a rational, atomistic illustration of the "two-site" binding paradigm in C5aR.
• To investigate the molecular dynamics of C5aR complexes with both the native agonist (hC5a) and an engineered antagonist (hC5a(A8)).
• To elucidate the mechanism of C5aR activation and the pharmacological divergence observed.

Main Methods:

• Molecular dynamics (MD) simulations of hC5a-C5aR and hC5a(A8)-C5aR complexes (250 ns each) within a POPC bilayer.
• Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations for binding free energy.
• Analysis of intermolecular interactions and correlation with existing mutational studies.

Main Results:

• Detailed atomistic insights into the hC5a-C5aR and hC5a(A8)-C5aR complex formation and dynamics.
• Validation of the "two-site" binding model through simulation data and binding free energy calculations.
• Demonstration of contrasting molecular interactions explaining the pharmacological divergence between agonist and antagonist binding.

Conclusions:

• The study provides a comprehensive, atomistic understanding of the C5aR activation mechanism.
• The findings rationalize the observed pharmacological differences in C5aR modulation.
• This knowledge is valuable for designing novel neutraligands targeting the hC5a-C5aR interaction for therapeutic purposes.