"Probing the Hydrogen Bonding Properties of the Protein-Water Interface and its Effects on Protein Stability, Function and Dynamics"

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The common component of all proteins is their aqueous solvent shell. Arguably, the most important role in protein structure and dynamics is played by the water solvent molecules. However (even after more than four decades of research), it is the role of water that remains the least understood of all. When a protein is dissolved in aqueous solvent it divides the solvent molecules into two groups: bulk water molecules and the molecules that constitute the protein hydration shell. Early experiments in protein hydration demonstrate that minimal hydration is required for protein structure and function pointing to the crucial role of the protein hydration sphere. The current research focus of my group is on understanding the role that solvent water molecules -especially those molecules located in the protein hydration sphere, play in ensuring proteins assume the correct fold and function. An extremely powerful method to better understand the role of the hydration sphere is to perturb the properties of these waters with chemical agents called osmolytes and subsequently determine the effect of this perturbation on the protein structure and function. Osmolytes are molecules produced by living organisms that stabilize proteins under highly denaturing conditions. Molecules such as TMAO (Trimethylamine N-oxide) stabilize the proteins by counteracting the effects of high concentrations of urea in the cells of marine organisms, while species such as betaine, sorbitol and inositol play a similar role in kidney cells. Although it has been known for a long time that osmolytes are strong stabilizers of the protein folded state, their mechanism of action on proteins is still not fully understood at the molecular level. However, most interpretations agree that the origin of osmolyte induced stabilization lies in the changes that these molecules effect on the hydration sphere. Understanding the mechanism by which osmolytes work will provide us with a framework for investigating the role of hydration water in crowded cellular environments, a long-term goal in our quest in understanding the role water plays in the biochemistry of real cells.