Free energy differences (in kcal/mol) for the described transformations.

<p>Error estimates are included.</p><p>^a Calculated as </p><p></p><p></p><p><mi>Δ</mi><mi>Δ</mi></p><p><mi>G</mi></p><p>MOP<mo>→</mo>HMP</p><p>exp<mo>.</mo></p><p></p><mo>=</mo><mi>Δ</mi><p><mi>G</mi></p><p>bind</p><p>HMP<mo stretchy="false">(</mo>exp<mo>.</mo><mo stretchy="false">)</mo></p><p></p><mo>−</mo><mi>Δ</mi><p><mi>G</mi></p><p>bind</p><p>MOP<mo stretchy="false">(</mo>exp<mo>.</mo><mo stretchy="false">)</mo></p><p></p><mo>=</mo><mi>R</mi><mi>T</mi>ln<p><mo>[</mo></p><p></p><p></p><p></p><p><mi>K</mi><mi>i</mi></p><p>HMP<mo stretchy="false">(</mo>exp<mo>.</mo><mo stretchy="false">)</mo></p><p></p><p></p><mo>/</mo><p></p><p><mi>K</mi><mi>i</mi></p><p>MOP<mo stretchy="false">(</mo>exp<mo>.</mo><mo stretchy="false">)</mo></p><p></p><p></p><p></p><p></p><mo>]</mo><p></p><mo>.</mo><p></p><p></p><p></p><p></p><p>Free energy differences (in kcal/mol) for the described transformations.</p

Molecular structures of morphine and hydromorphone.

<p>Molecular structures of morphine and hydromorphone.</p

Representative structure of the MD simulations for (A) the MOP-μOR and (B) the HMP-μOR complexes obtained from clustering analysis.

<p>The ligand carbon atoms are in orange. H-bonds and salt-bridges are shown in green and magenta dashed lines, respectively. For clarity hydrogen atoms of the ligands and the μOR residues are not shown. H297 is monoprotonated at the Nε atom.</p

Conformational change of μOR EL3 observed in the case of MOP binding.

<p>E310 in EL3 forms a salt-bridge with K233 (magenta dashed lines), which remains until the end of the simulation.</p

Schematic model of the agonist-induced μOR conformational change into an active-like state.

<p>Schematic model of the agonist-induced μOR conformational change into an active-like state.</p

The thermodynamic cycle for computing the free energy difference between MOP and HMP upon binding to μOR: ΔΔGbind=ΔGbindMOP−ΔGbindHMP=ΔGMOP→HMPbound−ΔGMOP→HMPunbound.

<p>The unbound state requires transformation of the ligands alone in solution, since the receptor is the same in both cases.</p

Arrangements of aromatic residues at the μOR orthosteric binding site upon binding with (A) MOP and with (B) HMP.

<p>Arrangements of aromatic residues at the μOR orthosteric binding site upon binding with (A) MOP and with (B) HMP.</p

Minimum distances between both morphinan drugs (MOP and HMP) and selected protein residues.

<p>Distances are given in Å and averaged over the finite temperature MD trajectories.</p><p>Minimum distances between both morphinan drugs (MOP and HMP) and selected protein residues.</p