CI2Daggett Research Group | Research | Protein Modulators

University of Washington - College of Engineering - School of Medicine - Department of Bioengineering

Selected Projects

Cofactors
Cosolvents
Glycosylation
Lipid Membranes

Protein Modulators

Protein stability and dynamics are influenced by both intrinsic factors (primary structure) and a variety of extrinsic factors. Primary structure (amino acid sequence) underlies the interactions that determine secondary, tertiary, and quaternary structure. These interactions determine how a protein folds. Therefore, amino acid sequence controls folding and stability. Proteins isolated from heat-adapted organisms, or thermophilic proteins, have primary sequences and three-dimensional structures similar to those from ordinary organisms (mesophilic proteins). However, thermophilic proteins are far more stable than their mesophilic homologues and have higher temperatures of optimal enzymatic activity. Current work in our group aims to characterize the dynamics of model thermophilic proteins and their mesophilic homologues and to explore the relationship between dynamics and function.

The stability and dynamics of proteins are also modulated by a variety of external factors (pH, co-solvents, lipid bilayer, etc.). Small-molecule chaotropic agents urea and guanidinium chloride unfold proteins, whereas the protective osmolytes trimethylamine N-oxide, glycerol, and trehalose increases stability. Our simulations of proteins in the presence of these "co-solvents" have yielded insight into their mechanisms of action at the molecular level. Other non-protein factors that influence protein dynamics include lipids (such as the lipid bilayer surrounding integral membrane proteins) and covalently attached carbohydrate groups (glycosylations). Including these molecules in simulations of disease-related proteins such as prion protein provides a realistic model of in vivo protein dynamics.

Relevant Publications