LABORATORY
OF PHYSICAL AND STRUCTURAL BIOLOGY
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V. Adrian Parsegian,
PhD, Chief The research
conducted by the Laboratory of Physical and Structural Biology (LPSB) is
motivated by the need to bring together many types of science. The next step
in structural biology is not simply to determine the structure of every
identifiable entity from molecule to organelle. Rather, it is to learn how
the structures work through the physics and chemistry of the intermolecular
forces that create them. Then, it will be possible to learn from the
increasing number of protein, nucleic acid, saccharide, and lipid structures
how to design agents that compete effectively with deviant interactions
associated with disease. Based
on observations of penicillins moving through protein channels, members of
the Section on Molecular Transport, led by Sergey Bezrukov, have
shown how attraction between channel and penetrating molecules improves the
probability of successful molecular traverse. Instead of drifting back out
the side it entered, an antibiotic attracted to the channel interior rattles
about long enough to forget which way it entered the channel. A 2 percent
likelihood of full traverse becomes a 50 percent chance of coming out the
other side, at only a small cost in time spent in the channel. Osmotic
stress measurements of specific versus nonspecific associations of proteins
with DNA have shown that sequences differing from the specific sequence by
even a single base pair bind only slightly better than completely random
sequences. Such an abrupt decrease in binding energy with even a single
base-pair change is accompanied by an abrupt increase in the water
sequestered by the protein-DNA complex. Stress studies conducted by Donald Rau’s group, the Section
on Macromolecular Recognition and Assembly, reveal the essential role of
dehydration in the tight fit needed for sequence recognition as well as the
importance of the ability to glide along the solvating water of nonspecific
associations until the protein finds its spot. Combining
computer computation with theoretical methods of solution chemistry has
allowed Adrian Parsegian’s
group, the Section on Molecular Biophysics, to develop a new
simulation method for swift modeling of protein folding under test tube and
cellular solution conditions rather than relying on the artificial conditions
of the usual simulation box. In parallel with the use of physical theory for
efficient computation, the section is measuring responses in molecular
association and the organization of lipids wrought by changes in the chemical
potential of neutral solutes and salts. |