Structure and nuclease activity of simple dinuclear metal complexes: Quantitative dissection of the role of metal ions

Enormous rate accelerations are necessary to hydrolyze RNA (108-fold) or DNA (1017-fold) within minutes. There are three direct modes of activation that media ions can provide for hydrolyzing phosphate diesters. The rate accelerations due to Lewis acid activation (<102-fold), intramolecular nucleophile activation (108-fold), and leaving group activation (106-fold) may in some cases combine simply to give an overall rate acceleration in excess of 1016-fold; in other cases, greater cooperatively between the models of catalysis is possible. Double Lewis acid activation obtained by coordinating both phosphoryl oxygens of a phosphate diester to a variety of dinuclear metal complexes (Figures 2 and 3) can give far greater rate accelerations for the hydrolysis reaction (4 x 105-fold for a dinuclear Co(III) complex) than single Lewis acid activation (<102). This mode of activation is possible with an intermetal distance from 2.9 to 7.0 Å and is particularly useful for cleaving RNA efficiently. For DNA hydrolysis, double Lewis acid activation by itself is not enough for efficient cleavage as it is about 109 times more stable than RNA. The nucleophile activation (metal hydroxide, metal alkoxide, metal-bridging oxide, metal-bridging peroxide) is important for DNA hydrolysis but not for RNA cleavage as its 2'- OH group already acts as a highly efficient internal nucleophile (Figure 1). However, the metal-activated nucleophiles may in some cases act as general base catalysts in cleaving RNA. While all of the above-mentioned nucleophiles can cleave phosphates with good leaving groups, only metal hydroxides appear to cleave those with poor leaving groups. For the other nucleophiles to be effective (metal alkoxide, metal-bridging oxide, metal-bridging peroxide), leaving group activation (coordination of the poor leaving group oxygen to the metal) is required.