DFT Computational
Study of the Methanolytic Cleavage
of DNA and RNA Phosphodiester Models Promoted by the Dinuclear Zn<sup>(II)</sup> Complex of 1,3-Bis(1,5,9-triazacyclododec-1-yl)propane
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Abstract
A density functional
theory study of the cleavage of a DNA model
[<i>p</i>-nitrophenyl methyl phosphate (<b>2</b>)]
and two RNA models [<i>p</i>-nitrophenyl 2-hydroxypropyl
phosphate (<b>3</b>) and phenyl 2-hydroxypropyl phosphate (<b>4</b>)] promoted by the dinuclear Zn<sup>(II)</sup> complex of
1,3-bis(1,5,9-triazacyclododec-1-yl)propane formulated with a bridging
methoxide (<b>1a</b>) was undertaken to determine possible mechanisms
for the transesterification processes that are consistent with experimental
data. The initial substrate-bound state of <b>2</b>:<b>1a</b> or <b>3</b>:<b>1a</b> has the two phosphoryl oxygens
bridging Zn<sup>(II)</sup><sub>1</sub> and Zn<sup>(II)</sup><sub>2</sub>. For each of <b>2</b> and <b>3</b>, four possible mechanisms
were investigated, three of which were consistent with the overall
free energy for the catalytic cleavage step for each substrate. The
computations revealed various roles for the metal ions in the three
mechanisms. These encompass concerted or stepwise processes, where
the two metal ions with associated alkoxy groups [Zn<sup>(II)</sup><sub>1</sub>:(<sup>−</sup>OCH<sub>3</sub>) and Zn<sup>(II)</sup><sub>1</sub>:(<sup>−</sup>O-propyl)] play the role of a direct
nucleophile (on <b>2</b> and <b>3</b>, respectively) or
where Zn<sup>(II)</sup><sub>1</sub>:(<sup>−</sup>OCH<sub>3</sub>) can act as a general base to deprotonate an attacking solvent molecule
in the case of <b>2</b> or the attacking 2-hydroxypropyl group
in the case of <b>3</b>. The Zn<sup>(II)</sup><sub>2</sub> ion
can serve as a spectator (after exerting a Lewis acid role in binding
one of the phosphates’ oxygens) or play active additional roles
in providing direct coordination of the departing aryloxy group or
positioning a hydrogen-bonding solvent to assist the departure of
the leaving group. An important finding revealed by the calculations
is the flexibility of the ligand system that allows the Zn–Zn
distance to expand from ∼3.6 Å in <b>1a</b> to over
5 Å in the transforming <b>2</b>:<b>1a</b> and <b>3</b>:<b>1a</b> complexes during the catalytic event