In this work a CASPT2//CASSCF/AMBER QM/MM approach was employed to investigate the isomerization and protonation reactions upon photoexcitation of the wild-type PYP.The study provides a comprehensive picture for the overall photocycle as illustrated in Scheme.The conical intersection CI(S1/S0)plays a critical role to bifurcate the excited state relaxation to the complete and short photocycles through different intermediates,IT [CI(S1/S0)like] and IT [pG(S0)like].Two major and one minor deactivation channels were found starting from the CI(S1/S0)like intermediate of IT,producing the cis isomers pR1,ICP,and ICT through the hula twist,bicycle pedal and one-bond flip isomerization reactions.The ICP→pB transition is achieved by high barrier bicycle pedal isomerization affiliating a fast protonation reaction of pCA chromophore through red shifted intermediate pR2.The high barrier decay of bicycle pedal followed by reverse one bond flip isomerizations lead to the hydrophobic-hydrophilic state transformation and the formation of high energy state pB,leaving a considerable spatial space between the pCA chromophore and Glu46.This allows the exposed COO-group of Glu46 to attract water solvent into the binding pocket through the slit between the surrounding protein residues and thus further triggers the fast deprotonation reaction for pCA chromophore.The photocycle is finally completed by the ground state recovery of phenoxy ring repelling water molecules out of the binding package through one bond flip isomerization with considerable high barrier.The kinetic analysis unveils that parallel mechanism through pR1→pB transition is favor channel but coexists with the sequential model via pR1→pR2 transformation.