Bond or cage effect: How nitrophorins transport and release nitric oxide
Most blood-sucking insects possess salivary proteins which, upon injection into the victim's tissue, help them improve their feeding. One group of these salivary proteins takes advantage of the vasodilator properties of NO to perform this task. These proteins are the so-called nitrophorins (NPs...
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todo:paper_00027863_v130_n5_p1611_Marti2023-10-03T13:54:05Z Bond or cage effect: How nitrophorins transport and release nitric oxide Martí, M.A. González Lebrero, M.C. Roitberg, A.E. Estrin, D.A. Blood-sucking insects Nitrophorins Salivary proteins Vasodilator properties Blood Coagulation Computer simulation Molecular dynamics Nitrogen compounds Proteins Tissue Biodiversity hemoprotein iron ligand nitric oxide nitrophorin saliva protein unclassified drug acidity alkalinity article binding affinity computer simulation conformational transition energy feeding insect molecular dynamics nonhuman protein conformation protein function validation process Computer Simulation Hemeproteins Hydrogen-Ion Concentration Models, Molecular Nitric Oxide Protein Binding Protein Structure, Tertiary Salivary Proteins Most blood-sucking insects possess salivary proteins which, upon injection into the victim's tissue, help them improve their feeding. One group of these salivary proteins takes advantage of the vasodilator properties of NO to perform this task. These proteins are the so-called nitrophorins (NPs). NPs are heme proteins that store and transport NO, which, when released in the victim's tissue, produces vasodilation and inhibition of blood coagulation. It has been proposed that NO binds tightly to NP at a low pH of around 5.6 and that once NPs are injected in the victims tissue, at a pH of approximately 7.4, a conformational change occurs which lowers NO affinity, allowing it to be released. In this work we have studied the NO release mechanism of NP4 at a molecular level using state of the art computer simulation techniques. We have used molecular dynamics (MD) simulations to study NP4 conformational dynamics at both pH values 5.6 and 7.4 and computed the corresponding free energy profile for NO release using a multiple steering molecular dynamics scheme. We also have used hybrid quantum mechanical/molecular mechanics (QM/MM) techniques to analyze the heme-NO structure and the Fe-NO bond strength in the different NP4 conformations. Our results provide the molecular basis to explain that NO escape from NP4 is determined by differential NO migration rates and not by a difference in the Fe-NO bond strength. In contrast to most heme proteins that control ligand affinity by modulating the bond strength to the iron, NP4 has evolved a cage mechanism that traps the NO at low pH and releases it upon cage opening when the pH rises. © 2008 American Chemical Society. Fil:Martí, M.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:González Lebrero, M.C. 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_00027863_v130_n5_p1611_Marti |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Blood-sucking insects Nitrophorins Salivary proteins Vasodilator properties Blood Coagulation Computer simulation Molecular dynamics Nitrogen compounds Proteins Tissue Biodiversity hemoprotein iron ligand nitric oxide nitrophorin saliva protein unclassified drug acidity alkalinity article binding affinity computer simulation conformational transition energy feeding insect molecular dynamics nonhuman protein conformation protein function validation process Computer Simulation Hemeproteins Hydrogen-Ion Concentration Models, Molecular Nitric Oxide Protein Binding Protein Structure, Tertiary Salivary Proteins |
| spellingShingle |
Blood-sucking insects Nitrophorins Salivary proteins Vasodilator properties Blood Coagulation Computer simulation Molecular dynamics Nitrogen compounds Proteins Tissue Biodiversity hemoprotein iron ligand nitric oxide nitrophorin saliva protein unclassified drug acidity alkalinity article binding affinity computer simulation conformational transition energy feeding insect molecular dynamics nonhuman protein conformation protein function validation process Computer Simulation Hemeproteins Hydrogen-Ion Concentration Models, Molecular Nitric Oxide Protein Binding Protein Structure, Tertiary Salivary Proteins Martí, M.A. González Lebrero, M.C. Roitberg, A.E. Estrin, D.A. Bond or cage effect: How nitrophorins transport and release nitric oxide |
| topic_facet |
Blood-sucking insects Nitrophorins Salivary proteins Vasodilator properties Blood Coagulation Computer simulation Molecular dynamics Nitrogen compounds Proteins Tissue Biodiversity hemoprotein iron ligand nitric oxide nitrophorin saliva protein unclassified drug acidity alkalinity article binding affinity computer simulation conformational transition energy feeding insect molecular dynamics nonhuman protein conformation protein function validation process Computer Simulation Hemeproteins Hydrogen-Ion Concentration Models, Molecular Nitric Oxide Protein Binding Protein Structure, Tertiary Salivary Proteins |
| description |
Most blood-sucking insects possess salivary proteins which, upon injection into the victim's tissue, help them improve their feeding. One group of these salivary proteins takes advantage of the vasodilator properties of NO to perform this task. These proteins are the so-called nitrophorins (NPs). NPs are heme proteins that store and transport NO, which, when released in the victim's tissue, produces vasodilation and inhibition of blood coagulation. It has been proposed that NO binds tightly to NP at a low pH of around 5.6 and that once NPs are injected in the victims tissue, at a pH of approximately 7.4, a conformational change occurs which lowers NO affinity, allowing it to be released. In this work we have studied the NO release mechanism of NP4 at a molecular level using state of the art computer simulation techniques. We have used molecular dynamics (MD) simulations to study NP4 conformational dynamics at both pH values 5.6 and 7.4 and computed the corresponding free energy profile for NO release using a multiple steering molecular dynamics scheme. We also have used hybrid quantum mechanical/molecular mechanics (QM/MM) techniques to analyze the heme-NO structure and the Fe-NO bond strength in the different NP4 conformations. Our results provide the molecular basis to explain that NO escape from NP4 is determined by differential NO migration rates and not by a difference in the Fe-NO bond strength. In contrast to most heme proteins that control ligand affinity by modulating the bond strength to the iron, NP4 has evolved a cage mechanism that traps the NO at low pH and releases it upon cage opening when the pH rises. © 2008 American Chemical Society. |
| format |
JOUR |
| author |
Martí, M.A. González Lebrero, M.C. Roitberg, A.E. Estrin, D.A. |
| author_facet |
Martí, M.A. González Lebrero, M.C. Roitberg, A.E. Estrin, D.A. |
| author_sort |
Martí, M.A. |
| title |
Bond or cage effect: How nitrophorins transport and release nitric oxide |
| title_short |
Bond or cage effect: How nitrophorins transport and release nitric oxide |
| title_full |
Bond or cage effect: How nitrophorins transport and release nitric oxide |
| title_fullStr |
Bond or cage effect: How nitrophorins transport and release nitric oxide |
| title_full_unstemmed |
Bond or cage effect: How nitrophorins transport and release nitric oxide |
| title_sort |
bond or cage effect: how nitrophorins transport and release nitric oxide |
| url |
http://hdl.handle.net/20.500.12110/paper_00027863_v130_n5_p1611_Marti |
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| _version_ |
1807321016505991168 |