  The binding of small metal ions to complex macromolecular structures is
typically dominated by strong local interactions of the ion with its nearest
ligands. For this reason, it is often possible to understand the microscopic
origin of ion binding selectivity by considering simplified reduced models
comprised of only the nearest ion-coordinating ligands. Although the main
ingredients underlying simplified reduced models are intuitively clear, a
formal statistical mechanical treatment is nonetheless necessary in order to
draw meaningful conclusions about complex macromolecular systems. By
construction, reduced models only treat the ion and the nearest coordinating
ligands explicitly. The influence of the missing atoms from the protein or the
solvent is incorporated indirectly. Quasi-chemical theory offers one example of
how to carry out such a separation in the case of ion solvation in bulk
liquids, and in several ways, a statistical mechanical formulation of reduced
binding site models for macromolecules is expected to follow a similar route.
Here, some critical issues with recent theories of reduced binding site models
are examined.
