Research
We are developing theoretical methods to reveal
mechanisms controlling conformational changes in
proteins relevant to biological function. We are
particularly interested in describing the
thermodynamics and kinetics of partially ordered of
conformational ensembles at the residue level.
Protein Folding
Proteins fold into the three-dimensional structures
essential to biological function. The modern
understanding of this molecular self-organization is
through the diffusive search on an energy landscape
in the shape of a funnel. The energy landscape
theory provides the general framework to understand
the physics underlying what makes proteins unique
macromolecules. Still, testing protein folding
theories requires comparison with experiments of
individual protein. We are developing models to
understand how to individual proteins fold. In
particular, we are interested characterizing the
mechanism controlling protein folding kinetics in
terms of partially ordered structural
ensembles. Recent topics include: cooperativity in
two-state folding proteins, describing folding in
terms of the evolution of the spatial density of
partially folded nuclei (transition state
ensembles), and kinetic signatures of downhill
folding and unfolding.
Allosteric transitions between meta-stable conformation
The key to understanding the biological function
of a folded protein often lies in it structural
flexibility and conformational dynamics. Flexibility
gives proteins the ability to respond to its cellular
environments and to other biomolecules such as
proteins, DNA, or membranes through binding induced
conformational changes. We are currently developing
general models inspired by work in protein folding to
understand the mechanisms controlling these
conformational changes. Initial focus is to explore
the influence of conformational flexibility on
structural transition kinetics, binding affinity, and
the kinetics of metal ion binding proteins such
calmodulin.
Coupled folding and binding
Perhaps the most extreme example of conformational
change due to interactions with other molecules is
when folding and binding are concomitant. Here, the
protein molecule is largely unfolded until it
interacts with its binding partner. The molecular
surface that induces folding can be another folded
protein, DNA, or a fluid membrane. We are particularly
interested in deeper understanding of the kinetic and
thermodynamic advantages associated with rapidly
growing list of natively unfolded proteins.