Hello, I'm Robert Tycko.
And in this talk,
I will tell you about recent work from
my laboratory in which we're using solid
state NMR to characterize the molecular
structures of amyloid and prion fibrils.
My research group is part of
the laboratory of chemical physics of
the National Institute of Diabetes and
Digestive and Kidney Diseases.
We're located on the main National
Institutes of Health campus in Bethesda,
In this talk,
I will describe work that was done by two
postdocs in my lab Anant Paravastu and
Sorin Luca, as well as work we're doing in
collaboration with Reed Wickner's Group,
also in NIDDK and a number of former
members of my group also contributed to
this work, including Oleg Antzutkin,
now at Lulea University in Sweden,
Who got this whole project started,
made the first amyloid fibril samples and
did the first solid state
NMR measurements in my lab.
Aneta Petkova, as you will see,
carried out many of the structural
measurements that led to a structural
model for the amyloid fibrils formed
by the beta amyloid peptide
associated with Alzheimer's disease.
Jerry Chan, John Balbach, Yoshitaka also
carried out important solid state NMR
measurements and helped to develop new
solid state NMR techniques that we've used
to characterize amyloid fibril structures
and Richard Leapman is an electron
microscopist at the NIH and we've been
collaborating with him as you will see,
electron microscopy measurements are very
important in providing information that's
complementary to the information
we get from solid state NMR.
Solid state NMR simply means the
application of nuclear magnetic resonance
spectroscopy to samples that are not
simple liquids or solutions.
Solid state NMR techniques are somewhat
different from the NMR techniques that
are used to determine the molecular
structures of soluble proteins.
And one of the reasons for the difference
is shown here of the left you see a one
dimensional proton NMR protein spectrum of
a small protein there are many many many
resolved proton NMR lines in this
one dimensional spectrum and
it's the fact that this one
dimensional spectrum so
well resolved that's largely responsible
for the success of multi dimensional
solution NMR techniques that are now
widely applied to protein structures.
On the right you see a solid state NMR
spectrum of a much smaller molecule,
a tripeptide Ala-Gly-Gly obtained
at our highest magnetic fields and
with high speed magic angle spinning,
a technique that narrows the NMR
lines as much as possible.
And still, you only see 3
resolved lines in the spectrum.
So the much poorer resolution in
the Proton NMR spectrum means that
the techniques that are used to determine
protein structures in solution really
don't apply to things like amyloid
fibrils, which are not soluble materials.
So the techniques and
the approaches that we used to investigate
molecular structures in solid state NMR
have to be different from those that
are commonly used in solution NMR.
Fortunately for us solid state NMR
techniques are applicable to a number
of systems and scientific problems that
cannot be addressed by solution NMR or
by other structural techniques.
And amyloid fibrils
are an excellent example of that.
In this talk,
I will say as little as possible about
the solid state NMR techniques themselves.
I'll try to focus on the information that
we've obtained with those techniques.
If you want to learn more about the solid
state NMR techniques I might suggest
you take a look at the quarterly reviews
of biophysics article listed here,
which gives an introduction
to those techniques.