The hexapeptide YPVEPF with strong sleep-enhancing effects
could
be detected in rat brain after a single oral administration as we
previously proved. In this study, the mechanism and molecular effects
of YPVEPF in the targeted stress-induced anxiety mice were first investigated,
and its key active structure was further explored. The results showed
that YPVEPF could significantly prolong sleep duration and improve
the anxiety indexes, including prolonging the time spent in the open
arms and in the center. Meanwhile, YPVEPF showed strong sleep-enhancing
effects by significantly increasing the level of the GABA/Glu ratio,
5-HT, and dopamine in brain and serum and regulating the anabolism
of multiple targets, but the effects could be blocked by bicuculline
and WAY100135. Moreover, the molecular simulation results showed that
YPVEPF could stably bind to the vital GABAA and 5-HT1A receptors due to the vital structure of Tyr-Pro-Xaa-Xaa-Pro-,
and the electrostatic and van der Waals energy played dominant roles
in stabilizing the conformation. Therefore, YPVEPF displayed sleep-enhancing
and anxiolytic effects by regulating the GABA-Glu metabolic pathway
and serotoninergic system depending on distinctive self-folding structures
with Tyr and two Pro repeats.