Enthalpic Breakdown of Water Structure on Protein Active-Site Surfaces

The principles underlying water reorganization
around simple nonpolar
solutes are well understood and provide the framework for the classical
hydrophobic effect, whereby water molecules structure themselves around
solutes so that they maintain favorable energetic contacts with both
the solute and the other water molecules. However, for certain solute
surface topographies, water molecules, due to their geometry and size,
are unable to simultaneously maintain favorable energetic contacts
with both the surface and neighboring water molecules. In this study,
we analyze the solvation of ligand-binding sites for six structurally
diverse proteins using hydration site analysis and measures of local
water structure, in order to identify surfaces at which water molecules
are unable to structure themselves in a way that maintains favorable
enthalpy relative to bulk water. These surfaces are characterized
by a high degree of enclosure, weak solute–water interactions,
and surface constraints that induce unfavorable pair interactions
between neighboring water molecules. Additionally, we find that the
solvation of charged side chains in an active site generally results
in favorable enthalpy but can also lead to pair interactions between
neighboring water molecules that are significantly unfavorable relative
to bulk water. We find that frustrated local structure can occur not
only in apolar and weakly polar pockets, where overall enthalpy tends
to be unfavorable, but also in charged pockets, where overall water
enthalpy tends to be favorable. The characterization of local water
structure in these terms may prove useful for evaluating the displacement
of water from diverse protein active-site environments.