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:
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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 victims 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 victims 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