Proximal effects in the modulation of nitric oxide synthase reactivity: A QM-MM study
Nitric oxide synthases (NOS) are heme proteins that have a cysteine residue as axial ligand, which generates nitric oxide (NO). The proximal environment, specifically H-bonding between tryptophan (Trp) 178 and thiolate, has been proposed to play a fundamental role in the modulation of NOS activity....
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todo:paper_09498257_v10_n6_p595_Fernandez2023-10-03T15:49:35Z Proximal effects in the modulation of nitric oxide synthase reactivity: A QM-MM study Fernández, M.L. Martí, M.A. Crespo, A. Estrin, D.A. Density functional theory Heme proteins Nitric oxide NOS QM-MM cysteine heme iron macrocyclic compound nitric oxide nitric oxide synthase protein sulfur tryptophan article calculation chemical bond comparative study electronics enzyme activity half life time modulation molecular biology priority journal quantum chemistry structure analysis Binding Sites Computational Biology Heme Hemeproteins Humans Hydrogen Bonding Iron Models, Molecular Nitric Oxide Synthase Type III Tryptophan Nitric oxide synthases (NOS) are heme proteins that have a cysteine residue as axial ligand, which generates nitric oxide (NO). The proximal environment, specifically H-bonding between tryptophan (Trp) 178 and thiolate, has been proposed to play a fundamental role in the modulation of NOS activity. We analyzed the molecular basis of this modulation by performing electronic structure calculations on isolated model systems and hybrid quantum-classical computations of the active sites in the protein environment for wild-type and mutant (Trp 178 × Gly) proteins. Our results show that in the ferrous proteins NO exhibits a considerable trans effect. We also showed that in the ferrous (Fe +2 ) mutant NOS the absence of Trp, experimentally associated to a protonated cysteine, weakens the Fe-S bond and yields five coordinate complexes. In the ferric (Fe +3 ) state, the NO dissociation energy is shown to be slightly smaller in the mutant NOS, implying that the Fe +3 -NO complex has a shorter half-life. We found computational evidence suggesting that ferrous NOS is favored in wild-type NOS when compared to the Trp mutant, consistently with the fact that Trp mutants have been shown to accumulate less Fe +2 -NO dead end species. We also found that the heme macrocycle showed a significant distortion in the wild-type protein, due to the presence of the nearby Trp 178. This may also play a role in the subtle tuning of the electronic structure of the heme moiety. © SBIC 2005. Fil:Fernández, M.L. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Martí, M.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Crespo, A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Estrin, D.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_09498257_v10_n6_p595_Fernandez |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Density functional theory Heme proteins Nitric oxide NOS QM-MM cysteine heme iron macrocyclic compound nitric oxide nitric oxide synthase protein sulfur tryptophan article calculation chemical bond comparative study electronics enzyme activity half life time modulation molecular biology priority journal quantum chemistry structure analysis Binding Sites Computational Biology Heme Hemeproteins Humans Hydrogen Bonding Iron Models, Molecular Nitric Oxide Synthase Type III Tryptophan |
| spellingShingle |
Density functional theory Heme proteins Nitric oxide NOS QM-MM cysteine heme iron macrocyclic compound nitric oxide nitric oxide synthase protein sulfur tryptophan article calculation chemical bond comparative study electronics enzyme activity half life time modulation molecular biology priority journal quantum chemistry structure analysis Binding Sites Computational Biology Heme Hemeproteins Humans Hydrogen Bonding Iron Models, Molecular Nitric Oxide Synthase Type III Tryptophan Fernández, M.L. Martí, M.A. Crespo, A. Estrin, D.A. Proximal effects in the modulation of nitric oxide synthase reactivity: A QM-MM study |
| topic_facet |
Density functional theory Heme proteins Nitric oxide NOS QM-MM cysteine heme iron macrocyclic compound nitric oxide nitric oxide synthase protein sulfur tryptophan article calculation chemical bond comparative study electronics enzyme activity half life time modulation molecular biology priority journal quantum chemistry structure analysis Binding Sites Computational Biology Heme Hemeproteins Humans Hydrogen Bonding Iron Models, Molecular Nitric Oxide Synthase Type III Tryptophan |
| description |
Nitric oxide synthases (NOS) are heme proteins that have a cysteine residue as axial ligand, which generates nitric oxide (NO). The proximal environment, specifically H-bonding between tryptophan (Trp) 178 and thiolate, has been proposed to play a fundamental role in the modulation of NOS activity. We analyzed the molecular basis of this modulation by performing electronic structure calculations on isolated model systems and hybrid quantum-classical computations of the active sites in the protein environment for wild-type and mutant (Trp 178 × Gly) proteins. Our results show that in the ferrous proteins NO exhibits a considerable trans effect. We also showed that in the ferrous (Fe +2 ) mutant NOS the absence of Trp, experimentally associated to a protonated cysteine, weakens the Fe-S bond and yields five coordinate complexes. In the ferric (Fe +3 ) state, the NO dissociation energy is shown to be slightly smaller in the mutant NOS, implying that the Fe +3 -NO complex has a shorter half-life. We found computational evidence suggesting that ferrous NOS is favored in wild-type NOS when compared to the Trp mutant, consistently with the fact that Trp mutants have been shown to accumulate less Fe +2 -NO dead end species. We also found that the heme macrocycle showed a significant distortion in the wild-type protein, due to the presence of the nearby Trp 178. This may also play a role in the subtle tuning of the electronic structure of the heme moiety. © SBIC 2005. |
| format |
JOUR |
| author |
Fernández, M.L. Martí, M.A. Crespo, A. Estrin, D.A. |
| author_facet |
Fernández, M.L. Martí, M.A. Crespo, A. Estrin, D.A. |
| author_sort |
Fernández, M.L. |
| title |
Proximal effects in the modulation of nitric oxide synthase reactivity: A QM-MM study |
| title_short |
Proximal effects in the modulation of nitric oxide synthase reactivity: A QM-MM study |
| title_full |
Proximal effects in the modulation of nitric oxide synthase reactivity: A QM-MM study |
| title_fullStr |
Proximal effects in the modulation of nitric oxide synthase reactivity: A QM-MM study |
| title_full_unstemmed |
Proximal effects in the modulation of nitric oxide synthase reactivity: A QM-MM study |
| title_sort |
proximal effects in the modulation of nitric oxide synthase reactivity: a qm-mm study |
| url |
http://hdl.handle.net/20.500.12110/paper_09498257_v10_n6_p595_Fernandez |
| work_keys_str_mv |
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1807317282864496640 |