Reactive Oxygen and Nitrogen Species at Phospholipid Bilayers: Peroxynitrous Acid and Its Homolysis Products

Peroxynitrite is
a powerful and long-lived oxidant generated in
vivo. Peroxynitrous acid (ONOOH), its protonated form, may penetrate
into phospholipid bilayers and undergo homolytic cleavage to nitrogen
dioxide (·NO2) and hydroxyl radicals (·OH), causing
severe nitro-oxidative damage. The membrane environment is thought
to influence ONOOH reactions, but the mechanisms remain speculative.
Most experimental techniques lack the level of resolution required
to keep track of the motion of very reactive species and their interactions
with the membrane. Here, we performed molecular dynamics simulations
of the permeation, interactions, and dynamics of ONOOH and its homolysis
products in the phospholipid membrane environment. We started by developing
an ONOOH model that successfully accounted for its conformational
equilibria and solvation energies. Membrane permeation of ONOOH was
accompanied by conformational changes. ONOOH exhibited a strong tendency
to bind to and accumulate at the membrane headgroup region. There,
ONOOH homolysis led to ·NO2 radicals, which in turn
partitioned to the membrane interior. About one-third of the ·OH
radicals readily escaped to the aqueous phase within 1 ns. However,
a significant number of ·OH radicals became trapped at the lipid
headgroup region for a longer period. The possible implications for
membrane-based nitration and oxidation processes were discussed.