Data from: Modeling stereospecific drug interactions with beta-adrenergic receptor

Beta-adrenergic receptors (βARs) are G protein-coupled receptors that
regulate processes such as heart rhythm and vascular tone by binding
agonists like norepinephrine, inducing downstream signaling pathways. Beta
blockers antagonize βARs, reducing heart rate and lowering vascular tone.
We developed a new Rosetta structural modeling protocol to create
state-specific models of β1AR and investigated its atomistic-scale
interactions with beta-blocker stereoisomers: d- and l-sotalol, as well as
R- and S-propranolol. Our combined molecular dynamics (MD) simulations and
docking protocol effectively captured the differences in stereoisomer
specificity in binding to β1AR. Binding energetics results favored
l-sotalol and S-propranolol, consistent with experimental findings showing
d-sotalol has significantly lower affinity for beta-adrenergic receptors
than l-sotalol. The entropy term was identified as the primary factor
driving enantiomer binding specificity, with higher entropy costs for
d-sotalol and R-propranolol due to their unfavorable chiral structures.
Simulations demonstrated that subtle differences in enantiomers lead to
distinct β1AR conformations, with d and R enantiomers causing larger
structural changes than l and S enantiomers. Specifically, sotalol affects
ICL2 and propranolol affects ICL1. The distance between TM4 and TM6 also
exhibited different distributions among enantiomers, indicating varying
strengths in stabilizing specific GPCR states. The outer vestibule of the
receptor may play a crucial role in the stereoselectivity of small drugs,
evidenced by fewer contacts between d-sotalol and ECL2 residues compared
to l-sotalol. This study provides a foundation for understanding the
stereospecificity of beta blockers for βARs, which are important
pharmacological targets, and could be extended to other drug classes and
receptor types.