Gábor Paragi

Telomere Structure and Stability: Covalency in Hydrogen Bonds, Not Resonance Assistance, Causes Cooperativity in Guanine Quartets

We show that the cooperative reinforcement between hydrogen bonds in guanine quartets is not caused by resonance-assisted hydrogen bonding (RAHB). This follows from extensive computational analyses of guanine quartets (G(4)) and xanthine quartets (X(4)) based on dispersion-corrected density functional theory (DFT-D). Our investigations cover the situation of quartets in the gas phase, in aqueous solution as well as in telomere-like stacks. A new mechanism for cooperativity between hydrogen bonds in guanine quartets emerges from our quantitative Kohn-Sham molecular orbital (MO) and corresponding energy decomposition analyses (EDA). Our analyses reveal that the intriguing cooperativity originates from the charge separation that goes with donor-acceptor orbital interactions in the σ-electron system, and not from the strengthening caused by resonance in the π-electron system. The cooperativity mechanism proposed here is argued to apply, beyond the present model systems, also to other hydrogen bonds that show cooperativity effects.

3-Substituted xanthines as promising candidates for quadruplex formation: computational, synthetic and analytical studies

Our computational studies suggest that 3-substituted xanthines are good candidates for tetrad and quadruplex structures. 3-Methylxanthine (3MX) has been synthesized from 7-benzylxanthine, and the existence of tetrameric and octameric aggregates of 3MX with NH4+, Na+ and K+ ions in the gas phase (MS) and in DMSO-d6 solution (NMR) has been observed. The “internal” H-bonds (N1H⋯O6) are stronger than the “external” ones (N7H⋯O2) in these clusters (NMR).

Ab initio studies on the H-bonding of hypoxanthine and DNA bases

Novel and interesting points are underlined by ab initio (QM) calculations of H-bonding of all the six nucleobase dimers of hypoxanthine and DNA bases, namely Hypanti⋯Asyn, Hypanti⋯Aanti, Hypsyn⋯Ganti, Hypanti⋯Gsyn, Hypanti⋯Tanti, Hypanti⋯Canti. HF, DFT (Becke) and B3LYP (hybrid-DFT) methods were applied with and without polarisation functions. The H-bonding preference of hypoxanthine to natural DNA bases is Gsyn>Canti>Aanti>Asyn>Tanti≈Ganti. Becke and B3LYP give buckle and propeller arrangements for Hoogsteen dimers, but the use of an auxillary basis set overestimates the angles. Hartree–Fock optimised structures are almost planar and this method does not find the local minima of Hoogsteen pairs. Among the methods giving reliable geometries the Becke calculation needs the least computational resources.

Neutral and positively charged new purine tetramer structures: a computational study of xanthine and uric acid derivatives

New tetramer structures, based on 9-methylxanthine (Xa), 9-methylxanthine protonated at N7 (XaH+) and 9-methyluric acid (Ua), were investigated by high-level density functional calculations. We have found that homo- and heterotetrads (XaH+)4, (XaH+–Xa)2, (XaH+–Ua)2 carrying positive charges can be formed by low barrier hydrogen bonds. Systems with zero charge [(Xa)4, (Xa–Ua)2, (Ua)4] were also constructed, investigated and compared to the guanine tetrad [(G)4]. It was shown that the new tetramers can bind cations and anions without the necessity of stacking interactions. Application of the calculated systems in higher-ordered structures (e.g. quadruplexes) is promising with or without intercalating ions.

Supramolecular H-bonded porous networks at surfaces: exploiting primary and secondary interactions in a bi-component melamine–xanthine system

The control over the formation of a bi-component porous network was attained by the self-assembly at a solid-liquid interface by exploiting both primary and secondary non-covalent interactions between melamine and N(3)-alkylated xanthine modules.

Self-assembly of n3-substituted xanthines in the solid state and at the solid–liquid interface

The self-assembly of small molecular modules interacting through noncovalent forces is increasingly being used to generate functional structures and materials for electronic, catalytic, and biomedical applications. The greatest control over the geometry in H-bond supramolecular architectures, especially in H-bonded supramolecular polymers, can be achieved by exploiting the rich programmability of artificial nucleobases undergoing self-assembly through strong H bonds. Here N(3)-functionalized xanthine modules are described, which are capable of self-associating through self-complementary H-bonding patterns to form H-bonded supramolecular ribbons. The self-association of xanthines through directional H bonding between neighboring molecules allows the controlled generation of highly compact 1D supramolecular polymeric ribbons on graphite. These architectures have been characterized by scanning tunneling microscopy at the solid-liquid interface, corroborated by dispersion-corrected density functional theory (DFT) studies and X-ray diffraction.

Investigation of exchange-correlation potentials in ensemble density functional theory: parameter fitting and excitation energy

Abstract The Gross–Oliviera–Kohns density functional theory (GOK-DFT) has been applied to ensembles consisting of 1st, 2nd and 3rd excited states of atoms. The main reason for the lack of widespread applications of GOK-DFT is the unknown explicit dependence of the exchange-correlation energy functional on the ensemble parameter (or weighting factor). In our investigations, the coefficient of the local term in the exchange-correlation functional has been determined requiring the calculated and the empirical ensemble energies to be equal. In calculations, different ground state approximations of the exchange and correlation functionals have been used and fitted to excited ensembles, and different expressions for the excitation energies have been tested and compared. Namely 1st, 2nd and 3rd excitation energies of He and Be have been calculated with ground state and with fitted X α , Becke, Gunnarsson–Lundqvist and Becke–Lee–Young–Parr functionals.

Computational understanding and experimental characterization of twice-as-smart quadruplex ligands as chemical sensors of bacterial nucleotide second messengers

A twice-as-smart ligand is a small molecule that experiences a structural switch upon interaction with its target (i.e., smart ligand) that concomitantly triggers its fluorescence (i.e., smart probe). Prototypes of twice-as-smart ligands were recently developed to track and label G-quadruplexes: these higher-order nucleic acid structures originate in the assembly of four guanine(G)-rich DNA or RNA strands, whose stability is imparted by the formation and the self-assembly of G-quartets. The first prototypes of twice-as-smart quadruplex ligands were designed to exploit the self-association of quartets, being themselves synthetic G-quartets. While their quadruplex recognition capability has been thoroughly documented, some doubts remain about the precise photophysical mechanism that underlies their peculiar spectroscopic properties. Here, we uncovered this mechanism via complete theoretical calculations. Collected information was then used to develop a novel application of twice-as-smart ligands, as efficient chemical sensors of bacterial signaling pathways via the fluorescent detection of naturally occurring extracellular quadruplexes formed by cyclic dimeric guanosine monophosphate (c-di-GMP).

Cooperativity in the Self-Assembly of the Guanine Nucleobase into Quartet and Ribbon Structures on Surfaces.

The guanine nucleobase can self-assemble into tetrameric or ribbon structures on surfaces or in solution. The origin for the occurrence of different aggregation patterns has not yet been investigated. Herein, a quantum chemical study on the different self-assembled structures of guanine and xanthine by using dispersion-corrected DFT is presented. Theoretical investigations can be used to explain, from an electronic point of view, the differences between the experimental findings. With quantitative Kohn-Sham molecular orbital theory and the accompanying energy decomposition analysis, the hydrogen-bonding mechanism within the guanine ribbons can be disclosed and the preferred self-assembled structures under different experimental conditions can be explained. An important role of the σ-electronic system in the guanine self-assembled structures is revealed as the main factor for the switch between different arrangements on surfaces and in crystals.

Supramolecular Ring Structures of 7-Methylguanine: A Computational Study of Its Self-assembly and Anion Binding

The density functional theory calculations of 7-methylguanine clusters revealed that stable ring assemblies can be formed with or without anions in the center position and hexameric clusters are the most stable and most planar ones. The coordination of anions (Cl−, Br−, NO3−) stabilizes and thus favors the formation of planar aggregates. We believe that the predicted planar structures stabilized by anions are good models for self-assembly structures formed at solid-liquid or solid-gas interfaces. Comparing the bonding and average H-bond energy to reference ribbon calculations we pointed out the presence of the previously introduced cooperativity effect in circular supramolecular structures of 7-methylguanine.