Modeling stereospecific drug interactions with beta-adrenergic receptors

Beta adrenergic receptors ({beta}ARs) are G protein-coupled receptors that control processes as varied as heart rhythm and vascular tone by binding agonists such as norepinephrine to induce downstream signaling pathways. Beta blockers antagonize {beta}ARs to downregulate their activity, thus reducing heart rate and lowering vascular tone. We developed new Rosetta structural modeling protocol to develop state-specific models of {beta}1AR, expressed in cardiac myocytes, as well as {beta}2AR, expressed in the smooth muscle cells of vasculature and other tissues, and their atomistic-scale interactions with beta-blockers using RosettaLigand. We identified structural features of drug - receptor interactions, which may account for their receptor conformational state and drug stereospecific preferences. Furthermore, we estimated structural stabilities of our models using atomistic molecular dynamics (MD) simulations. In our recent study we validated our structural models of norepinephrine-bound {beta}2AR and its complex with stimulatory G protein via multi-microsecond MD simulations. Thus, here we mostly focused on state-dependent and stereospecific {beta}1AR interactions with beta-blocking drugs sotalol and propranolol. We observed expected inactive receptor state preferences and structural stabilities of our models in MD simulations, but neither those simulations nor RosettaLigand docking could clearly distinguish stereospecific preferences of those drugs. This warrants consideration of alternative hypotheses and enhanced sampling MD simulations, which we discussed as well. Nevertheless, our study provides basis for understanding conformational state selectivity and stereospecificity of beta-blockers for {beta}ARs, important pharmacological targets, and may be extended to other drug classes and receptor types. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=157 SRC="FIGDIR/small/560334v1_fig0.gif" ALT="Figure 0"> View larger version (82K): org.highwire.dtl.DTLVardef@e8a838org.highwire.dtl.DTLVardef@7c2743org.highwire.dtl.DTLVardef@f5ac43org.highwire.dtl.DTLVardef@100a3d3_HPS_FORMAT_FIGEXP M_FIG Norepinephrine (NE) bound active-state beta-1 adrenergic receptor (1AR) in complex with the stimulatory G protein (Gs) heterotrimer embedded in a lipid bilayer. When expressed at the plasma membrane, the 1AR is oriented such that the ligand binding pocket (*) is accessible to ligands from the extracellular side (Ex.) of the membrane. The Gs (red), G (blue), and G{gamma} (yellow) subunits comprise the Gs heterotrimer. Nucleotides GDP or GTP bind G at the P-loop (**). Inset: Representative image of NE bound within the orthosteric ligand binding pocket. C_FIG