Current Activities

We are interested in how the biophysical properties of proteins are manifested in their biological function. The nature of internal protein motion and how this influences functions ranging from molecular recognition to allostery and catalysis is a particular focus. The view of protein thermodynamics and function has been largely driven by the exquisite detail of the structural models provided by crystallography and NMR spectroscopy. This is a very enthalpic view and ignores a potentially significant entropic component. Historically it has been impossible to experimentally determine the contribution of conformational entropy to fundamental protein activities such as the binding of ligands. We have recently developed an NMR-based “entropy meter” that employs a connection between motion and entropy. We are now exploring the role of entropy in a range of protein systems, particularly integral membrane proteins where little is known and the E3 ubiquitin ligase Parkin where we suspect that entropy is a dominating aspect of its regulation.

Despite tremendous technical advances in drug discovery, rational development of small molecule drugs is still difficult. Fragment based drug discovery (FBDD) offers great potential but has not penetrated the discovery space because “fragment” molecules are generally very weak binders. As a result, the enormous potential of fragment-based drug discovery is largely lost. Using the effects of the confined space of a reverse micelle we have developed an NMR-based method that is able to quantitatively detect weak binding. This capability could revolutionize early phase drug discovery.

To carry out these and several other related projects, along the way we have created novel capabilities such as high-pressure NMR, enhanced NMR-based hydrogen exchange methods, resonance assignment strategies, accelerated data acquisition and processing strategies, the reverse micelle encapsulation strategy discussed above and so on. High-pressure NMR is proving to offer many advantages in the context of protein biophysics, particularly with regard to understanding the thermodynamics and dynamics of proteins. to modern applications. NMR-sampling of hydrogen exchange provides access to site-resolved information about protein dynamics, folding and cooperativity.