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This study aimed to design and functionally characterize peptide mimetics of the nanobody (Nb) related to the β 2 -adrenergic receptor (β 2 -AR) (nanobody-derived peptide, NDP). We postulated that the computationally derived and optimized complementarity-determining region 3 (CDR3) of Nb is sufficient for its interaction with receptor. Sequence-related Nb-families preferring the agonist-bound active conformation of β 2 -AR were analysed using the informational spectrum method (ISM) and β 2 -AR:NDP complexes studied using protein-peptide docking and molecular dynamics (MD) simulations in conjunction with metadynamics calculations of free energy binding. The selected NDP of Nb71, designated P3, was 17 amino acids long and included CDR3. Metadynamics calculations yielded a binding free energy for the β 2 -AR:P3 complex of ΔG = (−7.23 ± 0.04) kcal/mol, or a Kd of (7.9 ± 0.5) μM, for T = 310 K.  In vitro  circular dichroism (CD) spectropolarimetry and microscale thermophoresis (MST) data provided additional evidence for P3 interaction with agonist-activated β 2 -AR, which displayed ~10-fold higher affinity for P3 than the unstimulated receptor (MST-derived EC 50  of 3.57 µM  vs . 58.22 µM), while its ability to inhibit the agonist-induced interaction of β 2 -AR with β-arrestin 2 was less evident. In summary, theoretical and experimental evidence indicated that P3 preferentially binds agonist-activated β 2 -AR.

Computational design and characterization of nanobody-derived peptides that stabilize the active conformation of the β2-adrenergic receptor (β2-AR)