INQUIMAE   12526
INSTITUTO DE QUIMICA, FISICA DE LOS MATERIALES, MEDIOAMBIENTE Y ENERGIA
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
molecular view of how Nitrophorin-4 releases Nitric Oxide in a pH dependent Manner as determined by computer simulation
Autor/es:
MARCELO A. MARTI
Lugar:
salta
Reunión:
Congreso; 3rd Latin American Protein Society Meeting (LAPSM),; 2010
Resumen:
<!-- @page { size: 8.5in 11in; margin: 0.79in } H1 { margin-top: 0in; margin-bottom: 0in; text-align: center } H1.western { font-family: "Nimbus Roman No9 L", serif; font-size: 14pt } H1.cjk { font-family: "DejaVu Sans"; font-size: 14pt } H1.ctl { font-family: "DejaVu Sans"; font-size: 12pt; font-weight: medium } H3 { margin-bottom: 0.04in } H3.western { font-family: "Nimbus Roman No9 L", serif; font-size: 12pt; so-language: en-US; font-weight: medium } H3.cjk { font-family: "DejaVu Sans"; font-size: 12pt; font-weight: medium } H3.ctl { font-family: "DejaVu Sans"; font-size: 12pt; font-weight: medium } P { margin-bottom: 0.08in } --> A molecular view of how Nitrophorin-4 releases Nitric Oxide in a pH dependent Manner as determined by computer simulation Marcelo A. Martia aDQIAyQF-INQUIMAE-CONICET y Dto de Química Biológica, FCEN, UBA, Cdad Univers, Pab 2, BsAs, C1428EHA, Argentina. E-mail:marcelo@qi.fcen.uba.ar 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. Using state-of-the-art computer simualtion techniques we have been able to determine: a) Why and how NO is released by NP4 at hig pH and b) How the key resiude pKa is finely tuned and coupled to the pH dependent conformational change. 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. Our results also show that key residue Asp30 pKa is conformational dependent, being about 4 (as expected by this resdiue type) in the high pH open conformation, but raises up to 8 in the closed conformation, ensuring its neutrality and retaining the protein in the closed state. Finally, the results for the pH dependent conformational change are discussed in the context of the population shift and allosteric model of allosterism. Marti MA. González Lebrero MC. Roitberg AE and Estrin DA.. J. Am. Chem. Soc,130(5); 1611-1618 .2008. Swails JM, Meng Y, Walker FA, Marti MA, Estrin DA, Roitberg AE. J Phys Chem B. 113(4):1192-201. 2009. Martí MA, Estrin DA, Roitberg AE. J Phys Chem B. 113(7):2135-2142, 2009