IQUIFIB   02644
INSTITUTO DE QUIMICA Y FISICOQUIMICA BIOLOGICAS "PROF. ALEJANDRO C. PALADINI"
Unidad Ejecutora - UE
artículos
Título:
Bond or Cage Effect: How Nitrophorins Transport and Release Nitric Oxide
Autor/es:
MARCELO A. MARTÍ, MARIANO C. GONZÁLEZ LEBRERO, ADRIÁN E. ROITBERG, AND DARIO A. ESTRIN
Revista:
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Referencias:
Año: 2008 p. 1611 - 1618
ISSN:
0002-7863
Resumen:
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.