On the nature of ion‐stabilized cytosine pairs in DNA i‐motifs: The importance of charge transfer processes

Abstract

Recent experimental results indicate that the stability of non‐Watson‐Crick DNA i‐motif structures can be influenced by the presence of various metal cations. Whereas Au+, Cu+, and Ag+ are stabilizing agents, alkali metal ions like Na+ or Li+ are known to destabilize the i‐motif. In terms of reduced ion‐cytosine complexes, we rationalize the experimental observations with the help of standard and conceptual density functional theory (DFT) calculations. Our results highlight the importance of coordinating electrostatic bonds with partially covalent character for the stability of the ion‐cytosine complex. The occurrence of these bonds can be mainly attributed to charge transfer processes between two cytosines and the transition metal ions, which can be either explained by frontier molecular orbital theory in combination with a bond critical point analysis, or by the concept of chemical reactivity indices within a conceptual DFT approach. The results of our calculations establish a consistent theoretical framework to understand the experimentally observed behavior, and are also important in order to achieve more detailed insights into nucleobase pairing mechanisms in general.

Theoretical Insights into Specific Ion Effects and Strong‐Weak Acid‐Base Rules for Ions in Solution: Deriving the Law of Matching Solvent Affinities from First Principles

“…[36,[47][48][49][50][51][52][53][54][55][56] Previous efforts in this direction [38,45,49,57,58] already revealed the many benefits of this straightforward approach. [11,21,44,50,58,59] Here, we outline the basic ideas and main concepts.…”

“…thereby contradicting Eqn. (21) and the fact that the hardness must have a positive value because of the convexity of the electron energy. [66] This situation is similar to that encountered in the case of the optimization of the hardness of the solvent.…”

“…[1][2][3]7,[13][14][15][16][17][18] In consequence, the aforementioned effects influence and modify various molecular mechanisms such as differences in ion pairing behavior, counterion condensation around polyelectrolytes, stability of protein formulations and the conductivity of electrolyte solutions. [2,7,[16][17][18][19][20][21][22] Despite the growing interest, the recent level of theoretical understanding regarding the underlying mechanisms is rather low. Advanced explanations focused on a combination of electrostatic interactions between the ions and short-range dispersion, polarization and solvation contributions.…”

“…[2][3][4]7] Besides the modification of electrostatic theories by consideration of polarization, dispersion as well as solvation contributions, recent papers highlighted the benefits of a conceptual density functional theory (DFT) approach in order to study specific ion effects. [11,12,21,35,36] Conceptual DFT is an analytic approach which was often used to provide rationales for chemical principles, reaction mechanisms, chemical reactivities as well as molecular properties. [36][37][38][39][40][41][42][43][44][45][46] The validity of a modified conceptual DFT approach for the study of various ion properties in distinct solutions was recently demonstrated.…”

Some Notes on the Thermodynamic Accuracy of Coarse-Grained Models

“…Although classical atomistic models provide a higher level of detail when compared to coarse-grained approaches, it has to be noted that the simplification of electronic behavior in terms of potential functions, so called force fields, introduces some conceptual artifacts into the dynamic and structural properties of the simulated molecular species (Dommert et al, 2012). Furthermore, polarization and charge-transfer mechanisms are usually ignored, such that more sophisticated ab initio or empirical models have to be used for systems where these effects become of importance (Smiatek et al, 2018; Kohagen et al, 2019; Nandy and Smiatek, 2019; Smiatek, 2019).…”