Figure 1.

Conserved polar/charged residues (in red; numbering as in MOR) that interacted with the -O and -OH groups of the N-phenethylnorhydromorphone body through H-bonds; the body was also stabilized by close packing with four conserved nonpolar residues (blue) through hydrophobic forces. Although not in direct interactions, a few non-conserved residues (green) were seen to interact with the ligands indirectly through short water chains. These residues may thus be important to modulate the behavior of MOR and DOR independently, which may be accomplished through specific substituents that can engage them more directly. Frequencies of contacts were deemed statistically relevant if they were observed at least 25% of the time, except for the critical -NH---D147 distance (MOR) and -NH---D128 distance (DOR) that was required to persist for at least 75% of the time for the conformer to be considered (see details of the analysis in Table S2).