The work in this laboratory takes a combined theoretical
and experimental approach to problems in structural
biophysics. Computer simulations play an increasingly
important role in our understanding of protein folding,
stability, activity, and the specificity of protein-ligand
interactions. Design methods are being developed which
can be used to rationally modify the structure and
function of a protein. This design methodology allows
us to ask very specific question firmly based on a
theoretical understanding of the system, which can
then be put to an experimental test. Computer programs
have been devised that build completely new active
sites into proteins of known structure. These are
being applied to building proteins with novel metal
centers and the rational manipulation of their chemical
reactivity. Work is also under way to build new enzyme
active sites to carry out reactions on organic substrates.
Another program has been developed which calculates
sets of sequences of optimal stability for a known
protein structure. The formalism of this approach
is very general and is being developed from the study
of protein ligand interactions such as receptor-ligand
systems, DNA-binding proteins, and drug design. The
experimental work involves molecular biology to construct
genes for the designed proteins, protein purification
methods and a variety of physical techniques t o study
the activity, stability and structure of the designed
proteins. Each design goes through several cycles
of iterative improvement involving design, analysis,
redesign, etc. Empirical improvement methods such
as genetic selection are also used where possible.
