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Water & Surfaces & Protein Folding
Overview In recent years, the
importance of understanding the dominant forces in protein folding has gained
wider appreciation as more scientists have recognized that misfolding of proteins may contribute to the pathology of certain
human diseases. Our primary research goal is to understand the forces that govern
the folding and stability of macromolecules under conditions that better mimic their
natural environment in a living cell. We are especially interested in the roles of
macromolecular crowding, confinement, and hydration effects due to perturbed water
structure. All of these factors may contribute to
the high fidelity of folding in vivo, but these phenomena are difficult
to investigate by the traditional approach of unfolding and refolding
biomolecules in dilute solution.
General Role of Bulk Water in Binding & Conformational Equilibria Our laboratory treats water explicitly as a co-reactant and
co-product for all aqueous reaction equilibria. A key motivating factor for this
treatment is the knowledge that water structure is altered at a boundary,
i.e. the network of hydrogen-bonded water molecules near a surface or solute
is perturbed relative to the bulk phase, and changes in the physical and
thermodynamic properties of water are expected to accompany this rearrangement.
For the hypothetical binding reaction shown below, a sphere of perturbed water
molecules surrounds reactant A, reactant B, and their product, complex AB. In
general, the average structure of the water within each sphere is altered
relative to the bulk water outside the sphere. The water molecules within the
spheres are given different colors to emphasize the fact that these water
molecules also differ from each other; the perturbed water structure will
reflect the specific surface chemistry of each reactant. At any given instant in
time, water molecules within a sphere of influence may leave to rejoin the bulk
phase, but a dynamic equilibrium exists such that the total numbers and
thermodynamic properties of the perturbed water molecules surrounding the
reactants and product are relatively constant. Furthermore, because the product
of this particular reaction exposes less surface area than the sum of the
reactants, a number of perturbed water molecules must be released to the bulk
phase (nH2O). For the diagram below, "n"
would denote the number of water molecules in the lens-shaped region of the
In the case of chemical reactions, where covalent bonds are
broken and/or formed, the solvent contribution to the total free energy change
of the reaction may be negligible. In the case of conformational equilibria or
binding equilibria, however, water may dictate the position of the equilibrium
for the overall reaction. Consequently, release of water to the bulk phase may
be extremely important in biological systems where nearly all reactions are
mediated by changes in conformation of, or binding to, macromolecules.
In
general, any aqueous equilibrium that involves exposure or burial of a surface
in contact with water may be subject to significant hydration effects, depending
on the magnitude of the free energy
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This website created by D.K. Eggers; comments
to daryl.eggers@sjsu.edu. |
