Binding between biomolecules is usually accompanied by the formation of
direct interactions with displacement of water from the binding sites.
In some cases, however, the interactions are mediated by ordered water
molecules, whose effect on binding affinity and the other thermodynamic
functions is unclear. In our work we compute the contribution of such water
molecules in different complexes to the thermodynamic properties using
statistical mechanical formulas for the energy and entropy. The requisite
correlation functions are obtained by molecular dynamics simulations. One water molecule we studied is the strongly bound water molecule at the binding site of
HIV-1 protease. We found that the entropic penalty of ordering is large but
is outweighed by the favorable water-protein interactions. We also found a
large negative contribution from this water molecule to the heat capacity.
Another water molecule we studied is buried at the binding interface of a
concanavalin A-carbohydrate complex. Besides the contribution of this water
molecule to the thermodynamic properties, other contributions to the binding
affinity, including desolvation, entropy of conformational restriction, and
interaction between the ligand and protein were also computed. The
thermodynamic consequences of displacement of the ordered water molecule by
ligand modification are in qualitative agreement with experimental data. The
free energy contribution of the water molecule (-17.2 kcal/mol; -19.2 enthalpic
and +2 entropic) is nearly equivalent to the additional protein-ligand
interactions in trimannoside 2 (-18.9 kcal/mol). The two structural ions
interact more strongly with the water than with the hydroxyl of trimannoside 2,
thus favoring trimannoside 1. The contributions from desolvation and
conformational entropy are much smaller but significant, compared to the
binding free energy difference. The picture that emerges is that the final
outcome of water displacement is sensitive to the details of the binding
site and cannot be predicted by simple empirical rules. Our approach could
be useful in rational drug design by estimating which bound water molecules
would be most favorable to displace.
