CHESTNUT HILL, MA (9-26-01) -- New findings from a team of chemists based at Boston College shed light on the role of the protein dynamics and solvent in protein function.
Drs. Martha Teeter, Akihito Yamano, Boguslaw Stec and Udayan Mohanty have demonstrated a critical role for water in enzyme (protein) function. Their findings could have positive ramifications for the design of many proteins -- from medicinals to laundry detergent enzymes -- making them more stable under adverse conditions such as acidity extremes or high temperature. Their research also offers insight into understanding the role of water in stabilizing non-pathogenic forms of proteins such as those associated with Alzheimer's disease.
The findings are published in the September 25 edition of Proceedings of the National Academy of Science, USA. ["On the Nature of a Glassy State of Matter in a Hydrated Protein: Relation to Protein Function" by M.M. Teeter, A. Yamano, B. Stec, and U. Mohanty. PNAS, 98, 11242-11247 (2001) ]
Drs. Teeter, Yamano, Stec and Mohanty have demonstrated through very high-resolution protein X-ray crystallography that protein and water adopt a glassy state at the same temperature that protein function ceases. This state, formed at 135 degrees F below zero (180 K), consists of clusters of protein surface atoms and solvent water that move in a coordinated fashion.
"Glasses are substances that become very viscous on approaching a glass transition temperature," said Dr. Teeter. "They were thought to adopt completely random arrays, which is why you can see through window glass. However, at a protein surface, the glass has a special character due to the polar (water-soluble) and non-polar (greasy) parts of the surface. Instead of being random, they form regions of cooperatively rearranging clusters of water and protein surface atoms. These results agree with water's glass-forming properties and suggest that disorder (entropy) decreases with decreasing temperature for the water/protein system below the glass transition temperature."
Since the early 1980s, protein surface atoms were described as having an ensemble of states with nearly equal energy, not a single arrangement at the surface. The present work lends functional importance to such ensembles at the protein surface and shows that water may provide the means for linking and coordinating these movable parts of the protein. The protein glass transition temperature can be influenced by salt, by the solvent properties or by the protein sequence, hence adapting the protein and the organism to function under a variety of conditions.
"We knew that organisms function at extreme conditions of temperature or salt in part because the proteins in them adapt and function under these adverse conditions," said Dr. Teeter. "The ability of a protein to function now has been connected both with the solvent around it and with its protein/water dynamics or mobility. Others have shown that dry proteins do not function, but now we understand that hydrating water must lubricate surface residues through cooperatively rearranging clusters so that surface residues will support function.
"Such glassy transitions would be important for the function of any solvated large biomolecule - proteins, DNA, RNA or polysaccharides," she added. "Based on these findings, protein and nucleic acid medicinals could be stored at low enough temperatures (below the glass transition) to inactivate them reversibly and protect them from contaminating enzymatic degradation or oxidation.
"Further, understanding the role of the protein surface residues in this glass transition permits proteins such as medicinals or laundry detergent enzymes to be designed that have longer half-lifes, i.e., are more stable under adverse conditions such as acidity extremes or high temperature.
"There are also implications of protein/water mobility for disease. Proteins that are hydrated by water maintain flexibility, as the present work shows. This ability of hydrated proteins to adopt several states may protect proteins from forming pathogenic aggregates, such as Alzheimer or prion amyloid and their analogs," said Dr. Teeter. "Such pathogenic forms of protein appear to exclude water as they self associate and form insoluble amyloid (Melinda Balbirnie, Robert Grothe, and David S. Eisenberg, (2001), "An amyloid-forming peptide from the yeast prion Sup35 reveals a dehydrated beta-sheet structure for amyloid" PNAS, 98 2375-2380). Thus, it may be possible to maintain the flexibility and hydration of proteins by adjusting surface conditions or by small ligands as therapeutics to prevent dehydration or aggregation."
[MEDIA NOTE: Principal author Dr. Martha Teeter, associate professor of chemistry at Boston College, can be reached directly at 530-752-3267 or 978-884-1471 or at 530-792-7185 (h). She currently is on leave in California and on Pacific time.]
Journal
Proceedings of the National Academy of Sciences