Rodríguez Mackenzie, Ángel David

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    Sulfmyoglobin formation pathway upon reaction of oxy-myoglobin and hydrogen sulfide
    (2019-12-03) Rodríguez Mackenzie, Ángel David; López Garriga, Juan; College of Arts and Sciences - Sciences; Meléndez, Enrique; Hernández Rivera, Samuel P.; Castro, Miguel; Department of Chemistry; Calcagno, Barbara
    Myoglobin (Mb) binds oxygen with high affinity as a low spin singlet complex and thus functions as an oxygen storage protein. Quantum chemical calculations of oxy-Mb models with hydrogen sulfide (H2S) in the active site predict that H2S can donate a hydrogen atom to the distal oxygen atom through homolytic cleavage of the S-H bond to form the intermediate Compound (Cpd) 0 structure and a hydrosulfide radical. In the presence of a mono-protonated His64-ε and H2S, Cpd 0 can be formed via the singlet state. The triplet state structures are energetically less favorable by ca. 10 kcal/mol. Surprisingly, the spin state preference is completely reversed at acidic pH (with doubly protonated His64-εδ) and in the presence of H2S, favoring the paramagnetic triplet state over the singlet state by 31-51 kcal/mol. In addition, the intermediate Cpd 0 is more stable with a positively charged His64. Typically, exotic techniques are required to generate Cpd 0 but under the conditions just described the intermediate is readily detected in UV-Vis spectra at room temperature. The effect is observed as a 2 nm red shift of the Soret band from 414 nm to 416 nm (pH 5.0, His64-εδ) and from 416 nm to 418 nm (pH 6.6, His64-ε). The occurrence of Cpd 0 in Oxy-Mb reaction with H2S sets the defining energy barrier for the concurrent formation of a Sulfheme species. Upon dissociation of Cpd 0 the recently generated *SH radical is integrated into the porphyrin over pyrrole B, resulting one of the three isomeric structures of SulfMb lowering the systems potential energy by approx. -81 kcal/mol. A Sulfheme formation mechanism was investigated from an Oxy-Mb stand point via QM/MM methods guided by experimental UV-Vis spectroscopic results. The proposed mechanism demonstrates plausible iii antioxidative properties during SulfMb formation, as radicals generated during Oxy-Mb autoxidative motion are consumed and prevented from further damaging the protein. Furthermore, due to the time dependent nature of the absorption spectra displayed by Sulfheme, the interplay between Met-aquoSulfheme isomeric structures was studied via Time Dependent Density Functional Theory (TDDFT). Sulfurs electron withdrawing effect as a peripheral substituent in the porphyrin results in the modulation of HOMO a1u and a2u orbitals of the porphyrin. Correlation with experimental UV-vis spectra acquired at different time regiments show that the predominant isomeric structures, 3-membered ring (SA) and 5-membered thiochlorin (SC), have different contributions in the absorption spectra for characteristic regions of 500, 620, and 700nm. Isomeric structure SA prevailing initially and SC at longer periods of time, a result that is consistent with the proposed reaction mechanism.