The Model Structures of the Complement Component 5a Receptor (C5aR) Bound to the Native and Engineered (h)C5a

The interaction of (h)C5a with C5aR, previously hypothesized to involve a “two-site” binding, (i) recognition of the bulk of (h)C5a by the N-terminus (NT) of C5aR (“site1”), and (ii) recognition of C-terminus (CT) of (h)C5a by the extra cellular surface (ECS) of the C5aR (“site2”). However, the pharmacological landscapes of such recognition sites are yet to be illuminated at atomistic resolution. In the context, unique model complexes of C5aR, harboring pharmacophores of diverse functionality at the “site2” has recently been described. The current study provides a rational illustration of the “two-site” binding paradigm in C5aR, by recruiting the native agonist (h)C5a and engineered antagonist (h)C5a(A8). The (h)C5a-C5aR and (h)C5a(A8)-C5aR complexes studied over 250 ns of molecular dynamics (MD) each in POPC bilayer illuminate the hallmark of activation mechanism in C5aR. The intermolecular interactions in the model complexes are well supported by the molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) based binding free energy calculation, strongly correlating with the reported mutational studies. Exemplified in two unique and contrasting molecular complexes, the study provides an exceptional understanding of the pharmacological divergence observed in C5aR, which will certainly be useful for search and optimization of new generation “neutraligands” targeting the (h)C5a-C5aR interaction.