Theoretical Insight into the Photodegradation of a Disulfide Bridged Cyclic Tetrapeptide in Solution and Subsequent Fast Unfolding−Refolding Events

Abstract

We report the photoinduced peptide bond (C-N) of an amide unit and S-S bond fission mechanisms of the cyclic tetrapeptide [cyclo(Boc-Cys-Pro-Aib-Cys-OMe)] in methanol solvent by using high-level CASSCF/CASPT2/Amber quantum mechanical/molecular mechanical (QM/MM) calculations. The subsequent energy transport and unfolding-refolding events are characterized by using a semiempirical QM/MM molecular dynamics (MD) simulation methodology that is developed in the present work. In the case of high-energy excitation with <193 nm light, the tetrapeptide molecule in the (1)n pi* surface overcomes two barriers with approximately 10.0 kcal/mol, respectively, and uses energy consumption for breaking the hydrogen bond as well as the N-C bond in the amide unit, ultimately leading to the ground state via a conical intersection of CI (S(NP)/S(0)) by structural changes of an increased N-C distance and a O-C-C angle in the amide unit (a two-dimensional model of the reaction coordinates). Following this point, relaxation to a hot molecule with its original structure in the ground state is the predominant decay channel. A large amount of heat (approximately 110.0 kcal/mol) is initially accumulated in the region of the targeted point of the photoexcitation, and more than 60% of the heat is rapidly dissipated into the solvent on the femtosecond time scale. The relatively slower propagation of heat along the peptide backbone reaches a phase of equilibration within 3 ps. A 300 nm photon of light initiates the relaxation along the repulsive S(sigma sigma)((1)sigma sigma*) state and this decays to the CI (S(sigma sigma)/S(0)) in concomitance with the separation of the disulfide bond. Once cysteinyl radicals are generated, the polar solvent of methanol molecules rapidly diffuses around the radicals, forming a solvent cage and reducing the possibility of close contact in a physical sense. The fast unfolding-refolding event is triggered by S-S bond fission and powered by dramatic thermal motion of the methanol solvent that benefits from heat dissipation. The beta-turn opening (unfolding) can be achieved in about 120 ps without the inclusion of the time associated with the photochemical steps and eventually relaxes to a 3(10)-helix structural architecture (refolding) within 200 ps.

A comprehensive study of isomerization and protonation reactions in the photocycle of the photoactive yellow protein

“…The formation of the hydrophilic state decreases the energy by more than 20 kcal mol À1 . This hydrogen bond stabilization energy is in good agreement with the previous experimental 82 and theoretical 83 estimates.…”

The Folding Dynamics and Infrared Spectra of a Photocleaved Tetrapeptide Predicted by Theoretical Simulations

“…In the methanol solvent, a 10e/9o active space is selected. 11 The orbitals and electrons are from the CO π, π*, the CN σ, σ*, and n lone pair in the peptide plane of the C6O5N3H4, the CO π, π* in the peptide plane of C9O8N10H1, and the SS σ, σ*.…”

Theoretical investigation of the degradation mechanisms in host and guest molecules used in OLED active layers

“…For example, facile decomposition of diphenyl sulfone (DPS) has been observed. [53][54][55][56][57] DPS and related compounds decompose via homolytic cleavage of one of the two formally single bonds connecting the sulfur atom to an aromatic ring, a process which characterized by an activation energy of 8.5-8.8 kcal/mol. 57 …”