We present a model describing how Mg2+ binds and stabilizes specific RNA st
ructures. In this model, RNA stabilization arises from two energetically di
stinct modes of Mg2+ binding: diffuse- and site-binding. Diffusely bound Mg
2+ are electrostatically attracted to the strong anionic field around the R
NA and are accurately described by the Poisson-Boltzmann equation as an ens
emble distributed according to the electrostatic potentials around the nucl
eic acid. Site-bound Mg2+ are strongly attracted to specifically arranged e
lectronegative ligands that desolvate the ion and the RNA binding site. Thu
s, site-binding is a competition between the strong coulombic attraction an
d the large cost of desolvating the ion and its binding pocket. By using th
is framework, we analyze three systems where a single site-bound Mg2+ may b
e important for stability: the P5 helix and the P5b stem loop from the P4-P
6 domain of the Tetrahymena thermophila group I intron and a 58-nt fragment
of the Escherichia coli 23S ribosomal RNA. Diffusely bound Mg2+ play a dom
inant role in stabilizing these RNA structures. These ions stabilize the fo
lded structures, in part, by accumulating in regions of high negative elect
rostatic potential. These regions of Mg2+ localization correspond to ions t
hat are observed in the x-ray crystallographic and NMR structures of the RN
A. In contrast, the contribution of site-binding to RNA stability is often
quite small because of the large desolvation penalty. However, in special c
ases, site-binding of partially dehydrated Mg2+ to locations with extraordi
narily high electrostatic potential can also help stabilize folded RNA stru
ctures.