We thank DST À Fast Track scheme, CSIR, and University Grants Commission (UGC) for partial funding. We thank Prof. M. Hariharan for fruitful discussions.

Stabilization of unstable mispairs on protonation in a DNA sequence can result in a change in the sequence conformation. Such sequences are being actively used for the synthesis of pH-driven molecular switches that have applications in biological pH sensing. We have studied various conformations of different mispairs of bases and their protonated forms using density functional theory (DFT) at B3LYP/6-31+G(d) and M05-2X/6-31+G(d,p) levels. Both gas-phase and aqueous-phase calculations are reported. Solvent phase calculations were done using the PCM and the COSMO solvation model. Our results show that the criterion for the protonation of a particular base in a mispair is not just its higher proton affinity. The planarity of the structure is significantly important, and a planar structure is energetically preferred over a bent mispair. Our calculations also show that the stabilization gained through protonation for the A-C, A-G, and the C-C mispairs is substantial (~20.0 kcal/mol); therefore, these are good candidates for pH-driven molecular switches.

Density Functional Tight Binding (DFTB) models are two to three orders of magnitude faster than ab initio and Density Functional Theory (DFT) methods and therefore are particularly attractive in applications to large molecules and condensed phase systems. To establish the applicability of DFTB models to general chemical reactions, we conduct benchmark calculations for barrier heights and reaction energetics of organic molecules using existing databases and several new ones compiled in this study. Structures for the transition states and stable species have been fully optimized at the DFTB level, making it possible to characterize the reliability of DFTB models in a more thorough fashion compared to conducting single point energy calculations as done in previous benchmark studies. The encouraging results for the diverse sets of reactions studied here suggest that DFTB models, especially the most recent third-order version (DFTB3/3OB augmented with dispersion correction), in most cases provide satisfactory description of organic chemical reactions with accuracy almost comparable to popular DFT methods with large basis sets, although larger errors are also seen for certain cases. Therefore, DFTB models can be effective for mechanistic analysis (e.g., transition state search) of large (bio)molecules, especially when coupled with single point energy calculations at higher levels of theory.

The structure and electronic properties of guanine oligomers and π stacks of guanine quartets (G-quartets) with circulene are investigated under an external field through first-principles calculations. An electric field induces nonplanarity in the guanine aggregates and also leads to an increase in the H-bond distances. The calculations reveal that the binding energy of the circulenes with G-quartets increases on application of an electric field along the stacking direction. The HOMO-LUMO gap decreases substantially under the influence of an external field. The contribution of a simple dipole-dipole interaction to the stability of the stacked system is also analyzed. The electric field along the perpendicular axis increases the dipole moments of the guanine dimer, trimer, and quartet. Such an increase in the dipole moment facilitates stacking with circulenes. The stability of G-quartet-circulene π stacks depends on the phase of the dipole moment (in-phase or out-of-phase) induced by an external electric field. The stability of stacks of bowl-shaped circulenes with G-quartets depends on the direction of the applied field.

While the Watson-Crick base pairs are known to stabilize the DNA double helix and play a vital role in storage/replication of genetic information, their replacement with non-Watson-Crick base pairs has recently been shown to have interesting practical applications. Nowadays, theoretical calculations are routinely performed on very complex systems to gain a better understanding of how molecules interact with each other. We not only bring together some of the basic concepts of how mispaired or unnatural nucleobases interact with each other but also look at how such an understanding influences the prediction of novel properties and development of new materials. We highlight the recent developments in this field of research. In this Perspective, we discuss the success of DFT methods, particularly, dispersion-corrected DFT, for applications such as pH-controlled molecular switching, electric-field-induced stacking of disk-like molecules with guanine quartets, and optical birefringence of alkali-metal-coordinated guanine quartets. The synergy between theoretical models and real applications is highlighted.

Recently, inorganic double-helical structures based on simple lithium and phosphorus salts have been demonstrated. We have analyzed the nature of bonding in these double helices of LinPn (n = 7-9). Similar to DNA, noncovalent interactions and cooperativity play an important role in stabilizing the inorganic double helices. Cooperativity imparts an additional stabilization of 4.5 to 10.1 kcal/mol per Li-P pair. In addition, the ionicity of Li-P units further augments the stability of these inorganic double-helix structures in contrast with the canonical base pairs in DNA, where noncovalent interactions determine the duplex stability. Unwinding is shown to be unfavorable, and cleavage of a few edge Li-P bonds leads to spontaneous self-healing into the intact double-helix tract.

The structures and proton-coupled behavior of adenine-thymine (A-T) and a modified base pair containing a thymine isostere, adenine-difluorotoluene (A-F), are studied in different solvents by dispersion-corrected density functional theory. The stability of the canonical Watson-Crick base pair and the mismatched pair in various solvents with low and high dielectric constants is analyzed. It is demonstrated that A-F base pairing is favored in solvents with low dielectric constant. The stabilization and conformational changes induced by protonation are also analyzed for the natural as well as the mismatched base pair. DNA sequences capable of changing their sequence conformation on protonation are used in the construction of pH-based molecular switches. An acidic medium has a profound influence in stabilizing the isostere base pair. Such a large gain in stability on protonation leads to an interesting pH-controlled molecular switch, which can be incorporated in a natural DNA tract.

A bacterial strain, GFAJ-1 was recently proposed to be substituting arsenic for phosphorus to sustain its growth. We have performed theoretical calculations for analyzing this controversial hypothesis by examining the addition of phosphate to ribose and glucose. Dispersion corrected Density Functional Theory (DFT) calculations in small molecules and QM/MM calculations on clusters derived from crystal structure are performed on structures involved in phosphorylation, considering both phosphates and arsenates. The exothermicity as well as the activation barriers for phosphate and arsenate transfer were examined. Quantum mechanical studies reveal that the relative stability of the products decrease marginally with successive substitution of P with As. However, simultaneously, the transition state barriers decrease with P replacement. This indicates that, kinetically, addition of As is more facile. Pseudorotation barriers for the pentavalent intermediates formed during the nucleophilic attack are also analyzed. A monotonic increase in barriers is observed for pseudorotation with the successive replacement of phosphorus with arsenic in methyl-DHP. A glucokinase crystal structure was chosen to construct a model system for QM/MM calculations. Free energy of the reaction (ΔG) reduces by less than 2.0 kcal/mol and the activation barrier (ΔG(‡)) decreases by ∼1 kcal/mol on arsenic incorporation. Thus, both DFT and QM/MM calculations show that arsenic can readily substitute phosphorus in key biomolecules. Secondary kinetic isotope effects for phosphorylation mechanism obtained by QM/MM calculations are also reported. The solvent kinetic isotopic effects (SKIE) for ATP and ATP (As) are calculated to be 5.81 and 4.73, respectively. A difference of ∼1.0 in SKIE suggests that it should be possible to experimentally determine the As-phosphorylation process.