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.
- Beck D.A.C., Bennion B.J., Alonso D.O.V., and Daggett V. Simulations of macromolecules in protective and denaturing osmolytes: properties of mixed solvent systems and their effects on water and protein structure and dynamics. Methods in Enzymology 428: 373-396, 2007. [DOI]
- DeMarco M.L. and Daggett V. Molecular Mechanism for Low pH-Triggered Misfolding of the Human Prion Protein. Biochemistry 46: 3045-3054, 2007. [DOI] [Hot Article]
- Bennion B.J. and Daggett V. Counteraction of urea-induced protein denaturation by trimethylamine N-oxide: A chemical chaperone at atomic resolution, Proceedings of the National Academy of Sciences USA 101: 6433-6438, 2004. [DOI]
- Bennion B.J., DeMarco M.L., and Daggett V. Preventing misfolding of the prion protein by Trimethylamine N-oxide, Biochemistry 43: 12955-12963, 2004. [DOI]
- Bennion B.J. and Daggett V. The Molecular Basis for the chemical denaturation of proteins by urea. Proceedings of the National Academy of Sciences USA 100: 5142-5147, 2003. [DOI]
- Zou Q., Bennion B.J., Daggett V., and Murphy K.P. The Molecular Mechanism of Stabilization of Proteins by TMAO and its Ability to Counteract the Effects of Urea. Journal of the American Chemical Society 125: 1192-1202, 2002. [DOI]