title: 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.
authors.affiliation: Department of Chemistry, Beijing Normal University, Xin-wai-da-jie #19, Beijing 100875, PR China. xuebochen@bnu.edu.cn
authors.forename: Xuebo
authors.initials: X
authors.lastname: Chen
authors.forename: Lianghui
authors.initials: L
authors.lastname: Gao
authors.forename: Weihai
authors.initials: W
authors.lastname: Fang
authors.forename: David Lee
authors.initials: DL
authors.lastname: Phillips
mesh_terms: D004220:Disulfides / Q000737:chemistry*; D000432:Methanol / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D010456:Peptides, Cyclic / Q000737:chemistry*; D010782:Photolysis; D011489:Protein Denaturation; D017510:Protein Folding; D012996:Solutions / Q000737:chemistry*; D013816:Thermodynamics; D014466:Ultraviolet Rays
chemical_list: D004220:Disulfides; D010456:Peptides, Cyclic; D012996:Solutions; C515705:cyclo(boc-Cys-Pro-Aib-Cys-OMe); D000432:Methanol