ISBN: 978-83-60043-10-3 - eurobic9

Eurobic9, 2-6 September, 2008, Wrocław, Poland
O2. Tracking Molecular Conformations of Cu-Zn Superoxide Dismutase
J.G. Grossmann a , C.W. Yong b , R.W. Strange a , S.V. Antonyuk a , M.A. Hough a , W. Smith b ,
S.S. Hasnain a
a
School of Biological Sciences, University of Liverpool, Crown Street, L769 7ZB, Liverpool, United Kingdom
e-mail: J.G.Grossmann@liverpool.ac.uk
b
Computational Science and Engineering Department, STFC Daresbury Laboratory, Keckwick Lane, WA4
4AD, Warrington, United Kingdom
More than 100 different mutations in the gene for Cu-Zn superoxide dismutase (SOD1) cause familial forms of
amyotrophic lateral sclerosis - a fatal neurodegenerative disease in which aggregation of the SOD1 protein is
considered to be the primary mode of pathogenesis [1]. SOD1 is active as a homodimer, containing one Cu and
one Zn per monomer. Each monomer folds into an eight-stranded antiparallel β-barrel connected by external
loops (see figure). Ala4Val, one of the most fatal mutations, causes a decrease in stability of the native
conformation yet without affecting metal binding or net charge [1].
Protein crystallography investigates structures of native and mutant proteins with differing metal content at
atomistic levels. However, the underlying dynamic mechanisms have to be inferred from these static studies in
crystalline forms and extrapolated to aqueous, physiological conditions. Hence the integration of X-ray
scattering [2] and molecular dynamics (MD) simulation [3] techniques offer a crucial complement to high
resolution crystallographic studies in understanding the molecular basis of protein destabilisation.
Here we report on MD calculations (to ≈20ns) of the fully solvated wild-type SOD1 and the Ala4Val mutant
protein in both the metal-free and metal-loaded states. The MD simulations are discussed in the light of X-ray
scattering data which show significantly larger conformational changes for Ala4Val SOD1 upon metal loss as
compared to the wild-type protein.
References:
[1] Valentine, J.S. et al. (2004) Copper-zinc superoxide dismutase and amyotrophic lateral sclerosis. Annu. Rev.
Biochem. 74, 563-593
[2] Hough, M.A. et al. (2004). Destabilisation of the dimer interface in SOD1 may result in disease causing
properties: Structure of motor neuron disease mutants A4V and I113T. Proc. Natl. Acad. Sci. U.S.A. 101, 5976-
5981
[3] Strange, R.W. et al. (2007). Molecular dynamics using atomic-resolution structure reveal structural
fluctuations that may lead to polymerization of human Cu-Zn superoxide dismutase. Proc. Natl. Acad. Sci.
U.S.A. 104, 10040-10044
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