Preorganization and predisposition are important molecular recognition concepts
exploited by nature to obtain site-specific and selective metal binding to
proteins. While native structures containing an MS3 core are often unavailable
in both apo- and holo-forms, one can use designed three-stranded coiled coils
(3SCCs) containing tris-thiolate sites to evaluate these concepts. We show that
the preferred metal geometry dictates the degree to which the cysteine rotamers
change upon metal complexation. The Cys ligands in the apo-form are preorganized
for binding trigonal pyramidal species (Pb(II)S3 and As(III)S3) in an endo
conformation oriented toward the 3SCC C-termini, whereas the cysteines are
predisposed for trigonal planar Hg(II)S3 and 4-coordinate Zn(II)S3O structures,
requiring significant thiol rotation for metal binding. This study allows
assessment of the importance of protein fold and side-chain reorientation for
achieving metal selectivity in human retrotransposons and metalloregulatory
proteins.
