Structure and dynamics of proteins, computational biology
The
overall goal of the research in our laboratory is to relate the
three-dimensional structure and dynamics of proteins to their
biological functions. We use techniques of X-ray crystallography and
electron microscopy to elucidate the molecular structures of proteins.
Extensive use is made of modern computational methods to analyze the
structures and their dynamics.
One research effort is
directed toward elucidating the precise molecular mechanisms of the
regulation of muscle contraction. The proteins which are involved in
the regulatory process have been identified and include: tropomyosin, a
highly helical molecule that forms filaments wound around actin, and
troponin, a complex consisting of three polypeptide chains, that binds
to tropomyosin. Detailed information about the structure of these
proteins is necessary before their roles in regulation can be
understood. We are also interested in the recognition of calcium by
muscle proteins, and have studied mutants of parvalbumin to dissect the
physical chemical principles involved in calcium signalling. The
technique best suited for obtaining this information is X-ray
crystallography.
Another project we have underway is
directed towards obtaining an atomic description of the basis for
binding of oxygen and other ligands to myoglobin. Detailed
three-dimensional structures are being determined for native and mutant
myoglobins with various ligands bound to the protein. We are moving
towards a quantitative understanding of the engineering of heme
proteins. The work is being extended to hemoglobin as potential
cell-free blood substitute.
Organisms have proteins that
are highly adapted to the growing conditions in the environment. We
have determined structures of enzymes from hyperthermophilic bacteria
to reveal aspects of the connections of protein structure to dynamics,
which is an integral part of proteins' designs.
We are
also working to develop new techniques for observing the dynamics of
proteins and nucleic acids using diffuse X-ray scattering analysis and
molecular dynamics simulations. The result will be a transition from
"snapshots" of macromolecules to the generation of "movies" of
molecules in action.
A new direction in our studies
includes computational biology. In particular, the use of modern
algorithms from computer science and applied mathematics to solve
interesting biological problems.