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.