Solvolysis Mechanisms of RNA Phosphodiester Analogues Promoted by Mononuclear Zinc(II) Complexes: Mechanisic Determination upon Solvent Medium and Ligand Effects

Abstract

The solvolysis mechanisms of RNA phosphodiester model 2-(hydroxypropyl)-4-nitrophenyl phosphate (HpPNP) catalyzed by mononuclear zinc(II) complexes are investigated in the paper via a theoretical approach. The general-base-catalyzed (GBC) and specific-base-catalyzed (SBC) mechanisms are thoroughly discussed in the paper, and the calculations indicate a SBC mechanism (also named as the direct nucleophilic attack mechanism) when the cyclization of HpPNP is promoted by the Zn:[12]aneN3 complex ([12]aneN3 = 1,5,9-triazacyclododecane). The ligand effect is considered by involving two different catalysts, and the results show that the increasing size catalyst provides a lower energy barrier and a significant mechanistic preference to the SBC mechanism. The solvent medium effect is also explored, and reduced polarity/dielectric constant solvents, such as light alcohols methanol and ethanol, are more favorable. Ethanol is proven to be a good solvent medium because of its low dielectric constant. The computational results are indicative of concerted pathways. Our theoretical results are consistent with and well interpret the experimental observations and, more importantly, provide practical suggestions on the catalyst design and selection of reaction conditions.

Phosphodiester models for cleavage of nucleic acids

“…All theoretical studies generally support a concerted reaction mechanism and indicate a number of important interactions to the nucleophile, phosphate and leaving group. Many of the studies concentrate also on the deprotonation of the nucleophile and both pre-equilibrium [ 200 , 211 ] and concerted processes [ 183 , 210 ] have been predicted. Regardless of timing, the nucleophile may also be coordinated to a metal ion [ 160 , 200 , 210 ].…”

The design of TACN-based molecular systems for different supramolecular functions

“…Alternatively, the deprotonation of hydroxyl takes place in a pre-equilibrium step and the nucleophilic attack features the rate determining step in a specific base catalytic mechanism (Fig. 25c) [72], it has been pointed out that the energetic barrier for the HPNP cleavage is similar in the two mechanisms, accounting for the difficulty to distinguish the two pathways in complexes with TACN derivatives. As a matter of fact, the effective mechanism and, consequently, the role of the metal in the catalyzed HPNP cleavage has been, and still is, subject of debate [68,72].…”

“…25c) [72], it has been pointed out that the energetic barrier for the HPNP cleavage is similar in the two mechanisms, accounting for the difficulty to distinguish the two pathways in complexes with TACN derivatives. As a matter of fact, the effective mechanism and, consequently, the role of the metal in the catalyzed HPNP cleavage has been, and still is, subject of debate [68,72]. Among different metal cations, the most commonly used has been Zn 2+ [67,70,71], due to its ubiquitous presence in hydrolytic metallo-enzymes.…”

Conformational Mobility and Efficiency in Supramolecular Catalysis. A Computational Approach to Evaluate the Performances of Enzyme Mimics

“…[15,16] Such artificial phosphodiesterases are typically based on the cooperation of metal cations acting as nucleophile carriers, Lewis acid activators, binding sites as well as promoters of the departure of leaving groups. [17][18][19][20][21][22][23][24][25] In spite of the widespread use of metals in these systems, a number of artificial (ribo)nucleases employ guanidinium groups as active functions on their own, [26][27][28][29] or in a synergic action with other active units. [30][31][32][33][34][35] The design of these catalysts has been inspired by nature since guanidinium is able to interact with several oxoanions, such as phosphates and carboxylates, [36,37] and play a primary role in the activity of enzymes with phosphodiesterase activity.…”

“…A relevant number of supramolecular catalysts were designed and synthesized to cleave phosphodiester bonds, due to their frequent presence in nature and to their reluctance to spontaneous hydrolysis , . Such artificial phosphodiesterases are typically based on the cooperation of metal cations acting as nucleophile carriers, Lewis acid activators, binding sites as well as promoters of the departure of leaving groups . In spite of the widespread use of metals in these systems, a number of artificial (ribo)nucleases employ guanidinium groups as active functions on their own, or in a synergic action with other active units .…”