Enthalpy–Entropy Trade-Off Underlies Geometric Isomer Selectivity in Histamine H1 Receptor–Doxepin Interaction

TL;DR

This study reveals how the histamine H1 receptor distinguishes between two forms of doxepin through differences in energy and entropy.

Contribution

The study directly measures thermodynamic differences between geometric isomers binding to a GPCR.

Findings

Z-isomer binding has higher enthalpy but lower entropy compared to E-isomer.

Mutant T1123.37V reduces the thermodynamic differences between isomers.

Conformational restriction explains the enthalpy–entropy trade-off in ligand binding.

Abstract

Understanding the thermodynamic basis of ligand recognition
by
G-protein-coupled receptors (GPCRs) is crucial for rational drug design.
Here, we directly characterized the binding thermodynamics of the
histamine H1 receptor (H1R) interacting with
the geometric isomers of doxepin using isothermal titration calorimetry
combined with molecular dynamics (MD) simulations. The Z-isomer binding to H1R_WT exhibited a larger enthalpic
gain but a greater entropic loss than the E-isomer,
whereas these differences were diminished in the T1123.37V mutant. Cluster analysis of MD trajectories revealed that Z-doxepin adopts a more restricted conformation upon binding,
consistent with its enthalpy-driven interaction and reduced conformational
entropy. These findings indicate that H1R distinguishes
between E- and Z-isomers not only
by affinity but also through distinct thermodynamic fingerprints.
This study provides mechanistic insight into the enthalpy–entropy
trade-off in GPCR–ligand interactions, highlighting the importance
of conformational restriction and flexibility in designing ligands
with optimized thermodynamic and functional properties.

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