Electrostatic versus Nonelectrostatic Effects in DNA Sequence Discrimination by Divalent Ions Mg²⁺ and Mn²⁺

Abstract

Mg 2+ and Mn 2+ ions are critical to the functioning of phosphoryl transfer enzymes, such as restriction endonucleases. Although these ions play similar roles in the chemical steps, they govern substrate specificity via modulating sequence discrimination by up to a factor of 10 5 with Mg 2+ and only up to a factor of 10 with Mn 2+ . To explain whether such diversity originates in fundamental differences in the electronic structures of the nucleobase-hydrated-metal ion complexes, structures and interaction energies were determined at the density functional (DFT) and second-order Møller-Plesset (MP2) levels of theory. Although both metal ions favor identical binding sites, Mn 2+ complexes exhibit greater distortions from the ideal octahedral geometry and larger variability than the corresponding Mg 2+ systems. In inner-shell complexes, with direct contact between the metal and the nucleobase, Mg 2+ is preferred over Mn 2+ in the gas phase, due primarily to nonelectrostatic effects. The interaction energies of the two metal ions are more similar in the outer-shell complexes, likely due to reduced charge transfer between the hydrated metal ion and the base moieties. Inclusion of solvation effects can amplify the relative nucleobase preferences of Mg 2+ and Mn 2+, indicating that bulk hydration modulates the balance between electrostatic and nonelectrostatic terms. In most cases, the base substitutions in solution are facilitated more by Mn 2+ than by Mg 2+. Electrostatic properties of the environment were demonstrated to have a major influence on the nucleobase preferences of the two metal ions. Overall, quantum chemical calculations suggest that the contrasting selectivity of Mg 2+ and Mn 2+ cofactors toward nucleobases derives from the larger flexibility of the Mn 2+ complexes accompanied by the excessive polarization and charge-transfer effects as well as less favorable solvation. IntroductionDivalent metal ions are critical to the proper functioning of various biomolecules. These ions can assemble and stabilize protein structures 1,2 and can induce complex formation with their substrates. 3,4 Many enzymes utilize them as cofactors to facilitate chemical conversions. [5][6][7] Divalent metal ions play a distinguished role in nucleic acid biochemistry. 8 In the catalytic machinery of enzymatic phosphoryl transfer, they act as Lewis acids to reduce the accumulation of negative charge in the transition state. 9-11 Divalent metal ions are crucial for folding of RNA as well as for the catalytic machinery of ribozymes. 12 Magnesium and calcium ions were reported to interfere with the structure of DNA in a sequence specific manner that is dependent on the ion type as well. 13 Mg 2+ ions primarily bind to phosphate groups of the DNA backbone via a solvent molecule in a so-called outer-shell mode. 14,15 Divalent metal ions were also observed to penetrate into the grooves, 16,17 where by crosslinking the base atoms of the opposite strands, they can modify the groove width and promote kinking of the DNA. Such sequence-spec...

Importance of Length and Sequence Order on Magnesium Binding to Surface-Bound Oligonucleotides Studied by Second Harmonic Generation and Atomic Force Microscopy

“…These results coincide with findings from bulk measurements that show that adenine is a weaker binder than guanine. 48,53,71,72 The lack of length dependency corroborates our earlier published findings that suggest the difference in free energies are due to variations in electron density of these surface-bound nucleobases. 42 Figure 2b shows that the number of Mg(II) ions bound depends linearly on guanine strand length.…”

Structural basis for ion selectivity revealed by high-resolution crystal structure of Mg2+ channel MgtE

“…Previous quantum chemical calculations of Mg 2+ and Mn 2+ in complex with water molecules revealed that the hydration geometry of the Mn 2+ ion deviates from the ideal octahedral arrangement, due to the excessive polarization and charge-transfer effects of Mn 2+ with open d orbitals3031. This difference between Mg 2+ and Mn 2+ was suggested to affect the substrate specificity of restriction enzymes32. We expect that this difference in the electronic states and polarization would also contribute to the difference in the affinities of the M1 site for Mg 2+ and Mn 2+ .…”

Influence of Mg2+ on the Guanine–Cytosine Tautomeric Equilibrium: Simulations of the Induced Intermolecular Proton Transfer

“…Although the Mg 2 + cation predominantly exists in its hexahydrated form [Mg(H 2 O) 6 ] 2 + in bulk water, it loses one water molecule when bonded to N7(G) of the nucleotide, and therefore five explicit water molecules are included to saturate the first hydration shell of the cation. [35] As recently advocated by Oliva and Cavallo for a similar model, [29] solvent effects beyond the first hydration shell should also be included to study ion-nucleic acid interactions. Consequently, the well-known polarizable continuum model (PCM) [36] was also included in our model following two strategies.…”