Protein dynamics and conformational disorder in molecular recognition and signaling

We study the relationship between conformational dynamics and function in proteins.

We develop methods in NMR spectroscopy to extract unique information at atomic resolution on conformational fluctuations that are critical for biological function — but invisible to other methods.

We use the experimental data to guide molecular dynamics simulations in order to derive detailed mechanistic pathways of molecular recognition and signaling.

We analyze the combined data using dynamic network analysis, information theory, and statistical thermodynamic theory to reach a new level of understanding in this field.

We have recently shown that our approach yields decisive answers to long-standing problems: the role of conformational entropy and solvation entropy in molecular recognition; the kinetic pathways and energy landscape of molecular recognition; the transmission pathways and energetics of allosteric signaling.

Each of these areas suggest new avenues for exciting approaches in drug design involving novel concepts: entropically optimized drugs, kinetically optimized drugs, and allosteric drugs.

A central theme in our vision is the innovative idea to rationally intervene in the dynamic information flow that occurs via transmission pathways formed by intra-protein interaction networks.Our project comprises the following specific aims:1. Decoding conformational entropy and information flow2.

Quantifying allosteric communication dynamics and energetics3. Mapping ligand binding pathways