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報告學生：彭家瑜 學號： 800260007 報告日期： 2013/03/04

Computational Design of Effective, Bioinspired HOCl Antioxidants: The Role of Intramolecular Cl + and H + Shifts. 報告學生：彭家瑜 學號： 800260007 報告日期： 2013/03/04. 出處： J. Am. Chem. Soc. 2012 , 134 , 19240–19245 作者： Amir Karton ,* Robert J. O’Reilly and Leo Radom*

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報告學生：彭家瑜 學號： 800260007 報告日期： 2013/03/04

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  1. Computational Design of Effective, BioinspiredHOCl Antioxidants: The Role of IntramolecularCl+ and H+ Shifts 報告學生：彭家瑜 學號：800260007 報告日期：2013/03/04

  2. 出處： J. Am. Chem. Soc. 2012, 134, 19240–19245 作者： Amir Karton,* Robert J. O’Reilly and Leo Radom* School of Chemistry, University of Sydney, Sydney, NSW 2006, Australia ARC Centre of Excellence for Free Radical Chemistry and Biotechnology David I. Pattison and Michael J. Davies Faculty of Medicine, University of Sydney, Sydney, NSW 2006, Australia Heart Research Institute, 7 Eliza Street, Newtown, NSW 2042, Australia ARC Centre of Excellence for Free Radical Chemistry and Biotechnology

  3. Abstract • Carnosine (肌肽) 普遍存在骨骼以及心臟的肌肉組織中，不足可透過飲食來攝取補充。過去研究發現carnosine 可有效清除體內的 HOCl，以至於當病原體攻擊身體細胞時，體內因保護機制所產生過多的 HOCl分 • 子不會累積在體內。 • 本研究透過理論模擬，計算 carnosine 和 HOCl 的部分反應機構，並根據計算結果，設計出類似的分子結構，但比 carnosine 反應效率更高。方法使用B3LYP/6-31G(2df,p) 計算結構，再以 G4(MP2) 理論進行能量上的校正，並根據 SMD 和 CPCM 兩種 solvation model，考慮反應在水中的溶劑效應。計算結果指出，carnosine 會根據三階段的分子內 (1) H 轉移，(2) Cl 轉移，(3) H 轉移的順序反應，形成一個熱力學穩定的分子，有助於 canosine 分子和 HOCl的反 • 應。本研究將 canosine 的 β-alanyl-glycyl (-CH2CH2NH2) 支鏈延長，成功使 Cl轉移的 barrier 從 110 kJ/mol 降低至 49 kJ/mol，總反應則從原本放熱 38 kJ/mol 增加至 42 kJ/mol，使得其分子和 HOCl反應更加容易進行。

  4. Introduction β-alanyl histidine imidazole The formula of carnosine • High concentrationsof carnosine are in skeleton, • heart muscle tissues, brain and eye lens. • Carnosine could be synthesized from the amino acids • β-alanine and histidine by the enzyme.

  5. Carnosine 可防止心臟病、癌症、糖尿病、阿茲海默症、帕金森氏症、骨質疏鬆、自閉症和白內障等慢性疾病的發生。亦可調節細胞內的 PH 值、減少移植器官所產生的過敏反應、可當作 Cu、Zn 離子的螯合劑。 Adv. Food Nutr. Res. 2009, 57, 87. Mol. Aspects Med. 1992, 13, 379. Carnosine 可作為抗氧化劑。 氧化劑例如：·OH、HOCl、ONOOH Int. J. Radiat. Biol. 1999, 75, 1177. Biochim. Biophys. Acta1998, 1380, 46. Mol. Aspects Med. 1992, 13, 379. 當人體遭到外來病原體攻擊時，體內酵素會催化 Cl-氧化，生成大量的 HOCl，再藉由 HOCl 的氧化反應攻擊病原體。然而過量的 HOCl會造成嚴重的發炎反應，對人體的 DNA 和蛋白質造成傷害。可能的傷害有：動脈硬化症、關節炎及部分的癌症。 而研究指出，carnosine 可清除體內過多的 HOCl。 Adv. Food Nutr. Res. 2009, 57, 87. Biochemistry2006, 45, 8152. Biochim. Biophys. Acta1998, 1380, 46.

  6. Chlorination of carnosine at the imidazole nitrogen and subsequent intramolecularCl transfer to the terminal primary amino nitrogen Mechanism? Kinetic measurements byPattisonand Davies Biochemistry2006, 45, 8152. Chem. Res. Toxicol. 2001, 14, 1453.

  7. The mechanism of intramolecularCl shift The four nitrogens in canosine N3 (amino nitrogen) N4 (amido nitrogen) N1 (imidazole nitrogen) N2 (imidazole nitrogen) Readily chlorinated by HOCl (Pattison et al.) N−Cl bond strength : imidazole < amine (-NH2) Calculations byO’Reilly, Karton and Radom J. Phys. Chem. A.2011, 115, 5496. Int. J. Quantum Chem. 2012, 116, 1862.

  8. Computational Methods For geometry and frequency calculations : SMD(water)-B3LYP/6-31G(2df,p) For the energy calculations : SMD(water)-G4(MP2) The combination of SMD(water)–M05–2X/6–31G(d) solvation correction on top of G4(MP2) energy CPCM(water)-G4(MP2) The combination of CPCM(water)–HF/6–31+G(d) solvation correction on top of G4(MP2) energy Program : Gaussian 03 and Gaussian 09

  9. Mean unsign error (MUE in kcal/mol) of several methods for G3/05 test set a DFT results based on single-point 6-311+G(3df ,2p) energies at MP2/6-31G* geometries with scaled 0.89 HF/6-31G* zero-point energies. b Relative CPU times of Gn methods for SiCl4, Benzene, Hexane andHeptane molecules. Curtiss et al. J. Chem. Phys. 2007, 127, 124105. J. Chem. Phys. 2005, 123, 124107.

  10. Results and Discussion Intramolecular rearrangements involved in the Cl+ transfer from the imidazole nitrogen (N2) to the terminal amino nitrogen (N3)

  11. Gibbs free-energy reaction profile for the intramolecularCl+ transfer in N-chlorinated carnosine (ΔG298, SMD(water)-G4(MP2), kJ mol−1). Atomic color scheme: H, white; C, gray; N, blue; O, red; Cl, green.

  12. Relative Gibbs free energies (ΔG298, kJ mol–1) for the local minima and transition structures with SMD and CPCM correction

  13. Candidates considered for HOCl-antioxidants with potentially reduced barriers for the intramolecularCl+ transfer. 2 carbons 5 carbons 4 carbons 3 carbons (Carnosine)

  14. Gibbs Free-Energy Barriers and Reaction Energies (ΔG‡298 and ΔG298, SMD(water)-G4(MP2), kJ mol-1) for the IntramolecularCl+ Transfer in the N-Chlorinated Derivatives of Carnosine and the Related Systems The intramolecularCl shift fails to occur in the carnosine−1 dipeptide. Experimental observation by Pattisonand Davies Biochemistry2006, 45, 8152.

  15. Transition structures at the SMD(water)-B3LYP/6-31G(2df,p) level for the intramolecularCl+ transfer in N-chlorinated carnosine. Atomic color scheme: H, white; C, gray; N, blue; O, red; Cl, green

  16. Conclusions • In this research, the possible mechanism of HOCl-scavenging for canosine was calculated at B3LYP/6-31G(2df,p) level with G4(MP2) energy correction. Solvent effects of water in the geometry and frequency calculations were included using SMD solvation model. • Based on their calculations, the authors proposed the mechanism for Cl+ shift and H+ shift in canosine. The barrier height for the Cl+ shiftwas found to be 110 kJ/mol. The overall reaction energy was found to be -38 kJ/mol. From the kinetically favored product to the thermodynamically favored product. • The results of energy with SMD correction and PCM correction are nearly the same.

  17. Increasing the length of the β-alanyl-glycyl side chain for canosine leads to the reduction of the barrier height (110 kJ/mol to 49 kJ/mol) for the Cl+ shift, and makes them react with HOCl more easier.

  18. Thanks for your attention !

  19. Supporting Information Comparison of β-alanine (right) with the more customary (chiral) amino acid, L-α-alanine (left)

  20. Supporting Information solvation correction

  21. Supporting Information G4 and G4(MP2) uses B3LYP/6-31G(2df , p) optimized geometries In G4(MP2): ΔE(HF) = E(HF/ limit) − E(HF/G3MP2LargeXP) In G4: The difference between G4 and G4(MP2): In G4(MP2), MP2 theory is used in place of MP4 theory. The core polarization functions of G3LargeXP are deleted in G4(MP2). The extrapolation E(HF/ limit) is based on aug-cc-pV(T+d)Z and aug-cc-pV(Q+d)Z, instead of aug-cc-pVQZ and aug-cc-pV5Z basis sets used in G4.

  22. Supporting Information G3 and G3(MP2) uses MP2(full)/6-31G(d) optimized geometries In G3(MP2): In G3: • E(G3) = E[QCISD(T)/6-31G(d)] + E(+) + E(2df) • +E(G3Large) + E(SO) + E(HLC) + E(ZPE) In G4(MP2): The difference between G3 and G3(MP2): The basis set extensions are obtained at the MP2 level, thus eliminating the MP4 calculations in G3(MP2). The core polarization functions of G3Large are deleted (G3MP2Large) in G3(MP2).

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