Arbelo López, Héctor D.

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    Sulfheme formation mechanism and spectra analysis using QM/MM and TDDFT
    (2018-05) Arbelo López, Héctor D.; López Garriga, Juan; College of Arts and Sciences - Sciences; Hernandez Rivera, Samuel P.; Vega Olivencia, Carmen A.; Santana, Alberto; Meléndez, Enrique; Department of Chemistry; Quiñones Padovani, Carlos
    Since the 1863 discovery of a new green hemoglobin derivative called “sulfhemoglobin”, the nature of its characteristic 618 nm absorption band and formation mechanism has been the subject of several hypotheses. Many heme-containing proteins with a histidine in the distal E7 (HisE7) position can form sulfheme in the presence of hydrogen sulfide (H2S) and a reactive oxygen species such as hydrogen peroxide. For unknown reasons, sulfheme derivatives are formed specifically on the solventexcluded heme pyrrole B. Here, the use of hybrid Quantum Mechanical/Molecular Mechanical (QM/MM) methods have permitted characterization of the entire process of sulfheme formation in the HisE7 mutant of hemoglobin I (HbI) from Lucina pectinata. This process includes a mechanism for H2S to enter the solvent excluded active site through a hydrophobic channel to ultimately form a hydrogen bond with H2O2 bound to Fe(III). Proton transfer from H2O2 to His64 to form Compound (Cpd) 0 followed by hydrogen transfer from H2S to Fe(III)-H2O2 complex results in homolytic cleavage of the O-O and S-H bond to form a reactive thiyl radical (HS•), ferryl heme compound II (Cpd II) and a water molecule. Subsequently, HS• addition to Cpd II followed by three proton transfer reactions results in the formation of a 3-membered ring ferric sulfheme (SA) that avoids the migration of the radical to the protein matrix in contrast to other peroxidative reactions. The transformation of SA to the 5-membered thiochlorin ring structure (SC) occurs through a significant potential energy barrier though both structures are nearly isoenergetic. Both SA and SC reveal a longer NB--Fe(III) bond than the other pyrrole nitrogen--Fe(III) bonds which would lead to a decreased in oxygen binding. The sulfheme experimental spectra are a function of the observation time, and interplay between two major sulfheme isomer concentrations (SA and SC); the latter being the dominant isomer at longer times. Thus, timedependent density functional theory (TDDFT) was used to calculate the sulfheme excited states and visualize the highest occupied molecular orbitals (HOMOs) and lowest unoccupied MOs (LUMOs) of both isomers in order to interpret the transitions between them. Formation of the three-membered ring SA and SC isomeric structures decrease the energy of the HOMO a1u and a2u orbitals compared to the unmodified heme due to the electron-withdrawing sulfur-containing ring. The calculations reveal that the absorption spectrum within the 700 nm region arises from a mixture of MOs, but can be characterized as π to π* transitions, while the 600 nm region is characterized by π to dπ (dyz, dxz) transitions having components of a deoxy like derivative. Overall, these results are in agreement with a wide range of experimental data and provide fertile ground for further investigations of sulfheme formation in other heme proteins, and additional effects of H2S on cell signaling and reactivity.
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    Detection of hydroperoxy complex in the oxidative reactions of myoglobin with hydrogen peroxide
    (2008) Arbelo López, Héctor D.; López Garriga, Juan; College of Arts and Sciences - Sciences; Vera Colón, Marisol; Cádiz García, Mayra E.; Department of Chemistry; Hernández Maldonado, Arturo
    A large number of heme enzymes catalyze the heterolysis of hydrogen peroxide (H2O2) and H2O2 is used as a source of oxidizing equivalents for biological oxidative reaction. Despite the increased understanding of the reactions of heme with H2O2, the hemehydroperoxy complex has never been identified at ambient temperature. To gain insight into this problem, we adapted laser flash photolysis spectroscopy with a stopped-flow rapid mixing device. This technique was used to probe the kinetic behavior of myoglobin with carbon monoxide in the presence of hydrogen peroxide, in the nano to microseconds timescale. Our results show for the first time that after photolysis a reaction intermediate, possibly the heme-hydroperoxide complex, is present at 426 nm, subsequently this intermediate species gives rise to the compound II species at 418 nm, respectively. The data allows suggesting a model where hydrogen peroxide binds to deoxyMb and forms the hydroperoxy species which give rise to the compound II species.