期刊
JOURNAL OF CHEMICAL INFORMATION AND MODELING
卷 60, 期 2, 页码 843-853出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jcim.9b00817
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资金
- Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET)
- Universidad de Buenos Aires [UBACYT 20020130100097BA]
- Agencia Nacional de Promotion Cientifica y Tecnologica [PICT 2014-1022, PICT 2015-2761]
- CONICET [11220150100303CO]
- Santander Ibero-America grant
- Agencia Nacional de Investigation e Innovation (ANTI), Uruguay
- Comision Sectorial de Investigation Cientifica (CSIC I+D 2016)
- Comision Sectorial de Investigation Cientifica (CSIC Grupos 2018)
- Espacio Interdisciplinario (Centros_2015)
- Universidad de la Republica, Ministerio de Education y Cultura (Fondo Vaz Ferreira 2018), Uruguay
- Centro de Biologia Estructural Mercosur (CeBEM)
- Centro de ComputaciOn de Alto Rendimiento (CeCAR) de la Facultad de Ciencias Exactas y Naturales de la UBA
- Programa de Desarrollo de Ciencias Basicas (PEDECIBA), Uruguay
In this work, we employ a multiscale quantum-classical mechanics (QM/MM) scheme to investigate the chemical reactivity of sulfenic acids toward hydrogen peroxide, both in aqueous solution and in the protein environment of the peroxiredoxin alkyl hydroperoxide reductase E from Mycobacterium tuberculosis (MtAhpE). The reaction of oxidation of cysteine with hydrogen peroxides, catalyzed by peroxiredoxins, is usually accelerated several orders of magnitude in comparison with the analogous reaction in solution. The resulting cysteine sulfenic acid is then reduced in other steps of the catalytic cycle, recovering the original thiol. However, under some conditions, the sulfenic acid can react with another equivalent of oxidant to form a sulfinic acid. This process is called overoxidation and has been associated with redox signaling. Herein, we employed a multiscale scheme based on density function theory calculations coupled to the classical AMBER force field, developed in our group, to establish the molecular basis of thiol overoxidation by hydrogen peroxide. Our results suggest that residues that play key catalytic roles in the oxidation of MtAhpE are not relevant in the overoxidation process. Indeed, the calculations propose that the process is unfavored by this particular enzyme microenvironment.
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