The distribution
in an egg–phosphatidylcholine bilayer of
a series of spin-labeled nitroxides, potentially useful as targeted
antioxidants, has been investigated using molecular dynamics (MD)
simulations. The in silico method has been tested at first for a series
of n-doxyl-phosphocholine-doped bilayers, with the
doxyl moiety located at different positions (n) of
the lipid chain, in analogy to electron paramagnetic resonance (EPR)
spin labeling and other MD studies. As a result, a novel calibration
curve has been obtained, suitable to determine the absolute membrane
penetration depth of any paramagnetic solute from EPR measurements.
A second series of MD simulations was then carried out on the newly
synthesized series of liponitroxides (NOXs) recently tested as antioxidants
against the lipid peroxidation of polyunsaturated fatty acids in membranes:
their penetration depths, as determined by EPR in phosphatidylcholine
liposomes, were correlated with their antioxidant efficacy. In these
NOXs, a glycerol moiety is esterified with a carboxy derivative of
a pyrroline nitroxide and one or two oleic acid residues. A very good
agreement between the EPR experimental results and those from the
current MD simulations indicates that the short distance of the nitroxide
moiety from the fatty acid double bonds has been now definitively
assessed; moreover, it indicates that our MD methodology could be
successfully employed in the absence of nonparamagnetic species.