The Role of the Hydroxyl Group in Propofol–Protein Target Recognition: Insights from ONIOM Studies

Propofol
(PFL, 1-hydroxyl-2,6-diisopropylbenzene) is currently
used widely as one of the most well-known intravenous anesthetics
to relieve surgical suffering, but its mechanism of action is not
yet clear. Previous experimental studies have demonstrated that the
hydroxyl group of PFL plays a dominant role in the molecular recognition
of PFL with receptors that lead to hypnosis. To further explore the
mechanism of anesthesia induced by PFL in the present work, the exact
binding features and interaction details of PFL with three important
proteins, human serum albumin (HSA), the pH-gated ion channel from Gloeobacter violaceus (GLIC), and horse spleen apoferritin
(HSAF), were investigated systematically by using a rigorous three-layer
ONIOM (M06-2X/6-31+G*:PM6:AMBER) method. Additionally, to further
characterize the possible importance of such hydroxyl interactions,
a similar set of calculations was carried out on the anesthetically
inactive fropofol (FFL, 1-fluoro-2,6-diisopropylbenzene) in which
the fluorine was substituted for the hydroxyl. According to the ONIOM
calculations, atoms in molecules (AIM) analyses, and electrostatic
potential (ESP) analyses, the significance of hydrogen bond, halogen
bond, and hydrophobic interactions in promoting proper molecular recognition
was revealed. The binding interaction energies of PFL with different
proteins were generally larger than FFL and are a significant determinant
of their differential anesthetic efficacies. Interestingly, although
the hydrogen-bonding effect of the hydroxyl moiety was prominent in
propofol, the substitution of the 1-hydroxyl by a fluorine atom did
not prevent FFL from binding to the protein via a halogen-bonding
interaction. It therefore became clear that multiple specific interactions
rather than just hydrogen or halogen bonds must be taken into account
to explain the different anesthesia endpoints caused by PFL and FFL.
The contributions of key residues in ligand–receptor binding
were also quantified, and the calculated results agreed with many
available experimental observations. This work will provide complementary
insights into the molecular mechanisms of anesthetic action for PFL
from a robust theoretical point of view. This will not only assist
in interpreting experimental observations but will also help to develop
working hypotheses for further experiments and future drug design.