Intermolecular Interactions in G Protein-Coupled Receptor Allosteric Sites at the Membrane Interface from Molecular Dynamics Simulations and Quantum Chemical Calculations

Allosteric modulators are called promising candidates
in G protein-coupled
receptor (GPCR) drug development by displaying subtype selectivity
and more specific receptor modulation. Among the allosteric sites
known to date, cavities at the receptor–lipid interface represent
an uncharacteristic binding location that raises many questions about
the ligand interactions and stability, the binding site structure,
and how all of these are affected by lipid molecules. In this work,
we analyze interactions in the allosteric sites of the PAR2, C5aR1,
and GCGR receptors in three lipid compositions using molecular dynamics
simulations. In addition, we performed quantum chemical calculations
involving the symmetry-adapted perturbation theory (SAPT) and the
natural population analysis to quantify the strength of intermolecular
interactions. We show that besides classical hydrogen bonds, weak
polar interactions such as O–HC, O–Br, and long-range
electrostatics with the backbone amides contribute to the stability
of allosteric modulators at the receptor–lipid interface. The
allosteric cavities are detectable in various membrane compositions.
The availability of polar atoms for interactions in such cavities
can be assessed by water molecules from simulations. Although ligand–lipid
interactions are weak, lipid tails play a role in ligand binding pose
stability and the size of allosteric cavities. We discuss physicochemical
aspects of ligand binding at the receptor–lipid interface and
suggest a compound library enriched by weak donor groups for ligand
search in such sites.