Chemistry Reference
In-Depth Information
Figure 1.2
The nucleobase-metal-phosphate linkage in the crystal structure of Cu(5
′
-
GMP)
4
Such complexes may be used as drugs that block specifi c gene expression associated
with a certain disease.
Metal ions can interact with nucleic acids in two distinct modes of binding:
diffuse binding and site binding, both of which are important for the structure and
function of nucleic acids.
11a,b
In the diffuse binding mode the metal and the nucleic
acid retain their hydration layer and the interaction is through water molecules.
11c
This is a long-range Coulombic interaction, in which positive metal ions accumulate
around the nucleic acid in a delocalized manner; for example, the counterion atmos-
phere that all nucleic acids possess is made up of diffusely bound positive ions. In
the site-binding mode the metal is coordinated to specifi c ligands on the nucleic
acid; the coordination can either be direct (termed inner-sphere) or through a water
molecule (termed outer-sphere). In the outer-sphere binding mode only the inner-
most hydration layer of the metal is kept intact, and the metal and the nucleic acid
ligand(s) to which the metal is coordinated share solvation shells. In inner-shell
binding there is direct contact between the metal and the nucleic acid. Dehydration
of the metal ion and the nucleic acid binding site therefore has to occur before an
inner-shell bond is formed.
The mechanism of inner-sphere binding is likely to be initiated by a diffuse
binding mode, in which the metal and the nucleic acid are separated by no more
than two layers of solvent molecules.
11d
This step is diffusion controlled. The next
step is that the metal ion and the nucleic acid form an outer-sphere complex, sepa-
rated only by one layer of solvent molecules. This step primarily depends on elec-
trostatic attractions and hydrogen bonding between the metal and the nucleic acid.
12
In the fi nal step the metal and the nucleic acid come into direct contact (inner-
sphere binding). Here the nucleophilicity of the coordination site plays a crucial
role. In the last two steps steric effects are also important. Several attempts have
been made to quantify the importance of accessibility and molecular electrostatic
potential (MEP) at the site where the inner-sphere complex/covalent bond is
formed.
13,14
In these studies a reasonable correlation between these two important
