Ariz. – A team of researchers have developed a method
that could vastly improve the ability of atomic force
microscopes to "see" the chemical composition
of a sample, follow variations of the sample, as well
as map its topographic structure.
The advance could have significant implications for
drug development by allowing scientists to monitor
the effects of potential drugs on an ever-smaller
scale, according to Stuart Lindsay, director of the
Center for Single Molecule Biophysics at the Biodesign
Institute at Arizona State University and a lead researcher
on the project.
Lindsay, an ASU professor in the department of physics
and astronomy said the new technique allows an atomic
force microscope to "see," on a nanometer
scale, the chemical composition of molecules.
"Atomic force microscopy has a resolution down
to an atomic level, but until now it has been blind
to identifying specific chemical compositions,"
The researchers -- Lindsay, Hongda Wang, Ralph Bash,
Brian Ashcroft, and Dennis Lohr of Arizona State University;
Cordula Stroh, Hermann Gruber and Peter Hinterdorfer
of the Institute of Biophysics at the University of
Lintz, Austria; and Jeremy Nelson of Molecular Imaging
Corporation, Tempe, Ariz. -- present their findings
in "Single Molecule Recognition Imaging Microscopy"
in the current issue of the Proceedings of the National
Academy of Sciences. The article is available on line
"If you imagine that all proteins are shaped
like Lego blocks, then conventional atomic force microscopy
(AFM) is feeling the Lego blocks on the floor, but
it can't tell the difference between one block and
another," Lindsay explained. "What we have
done, is allow the person sitting on the floor and
feeling those blocks to open their eyes and see that
there are red Lego blocks, green Lego blocks and yellow
"This allows you to identify specific components
in an image," he added. "It means you can
now follow a complex process and see what's happening,
at the molecular level, to one of the components.
We are now giving AFM chemical sensitivity in much
the way colored dyes gave optical microscopes optical
sensitivity for much larger objects (~1 micron)."
Atomic force microscopes provide images on the nanometer
scale by using a highly sensitive and tiny probe that
is essentially pulled across a surface. By doing this,
researchers can obtain topographical images down to
a nanometer scale.
To use the AFM in its new mode, the researchers attached
antibodies keyed to individual proteins to the tip
of an AFM's probe. When an antibody reacts with the
protein it is specifically targeted for, it creates
a variance in the microscope's reading compared to
a reading with a bare tip, thus showing the presence
of a protein or other specific material in the region
To help ensure that the antibody tipped probe is truly
sensitive, a strand of polymer connects the antibody
to the tip, providing a tether that allows the antibody
to wiggle into position to better connect with the
protein receptors. A magnetically excited cantilever
makes the tip oscillate up and down to make the antibody
disconnect and reconnect and keep the probe moving.
A key capability of this technique, Lindsay said,
is that it allows researchers to see how components
of a cell react on a molecular scale when they experience
biological processes, such as their response to a
specific chemical or compound. In this mode, it could
provide researchers with a molecular "time-lapsed
movie" of such reactions, which could lead to
greater understanding of the chemical dynamics involved
in how cells react to such stimuli.
Lindsay said the new AFM method could be significant
for drug discovery.
"This development opens up the AFM as a research
tool," Lindsay added. "The ability to identify
the specific proteins on a membrane surface means
you can take something very complex, like the surface
of a human cell with all of the types of different
receptors on it and ask questions about the local
chemistry, like what is binding at those sites. That
will provide the fundamental knowledge you need to
develop new drugs."
Media contact: Skip Derra, (480) 965-4823; firstname.lastname@example.org
Source: Stuart Lindsay, (480) 965-4691