Weak Supramolecular Interactions Governing Parallel and Antiparallel DNA Quadruplexes: Insights from Large‐Scale Quantum Mechanics Analysis of Experimentally Derived Models

Abstract

The topology and energetics of guanine (G) quadruplexes is governed by supramolecular interactions within their strands. In this work, an extensive quantum mechanical (QM) study has been performed to analyze supramolecular interactions that shape the stems of (4+0) parallel (P) and (2+2) antiparallel (AP) quadruplex systems. The large-scale (≈400 atoms) models of P and AP were constructed from high-quality experimental structures. The results provide evidence that each of the P and AP structures is shaped by a distinct network of supramolecular interactions. Analysis of electron topological characteristics of hydrogen bonds in P and AP systems indicates that the P model benefits from stronger intratetrad hydrogen bonding. For intertetrad stacking interactions, both noncovalent interaction plot and energy decomposition analysis approaches suggest that the stem of the P quadruplex benefits more from stacking than that of the AP stem; the difference in energetic stabilization for the two topologies is about 10 %. Stronger hydrogen-bonding and stacking interactions in the stem of the P quadruplex, relative to those in the AP system, can be an important indicator to explain the experimental observations that guanine-rich oligonucleotides tend to form all-parallel stems with an all-anti orientation of nucleobases. However, in addition to intrinsic stabilization, partial desolvation effects, which affect the energetics and dynamics of the G-quadruplex folding process, call for further investigations.

RNA versus DNA G‐Quadruplex: The Origin of Increased Stability

“…Twoo rm ore tetrads can stacko nt op of each other due to the contribution of electrostatic and dispersion forces. [10,11] Sugar-phosphate moieties of guanosine monomers constitute the outer backbone of these structures and contribute to their stability ( Figure 2). Loops, with variouss equences and length, connectt he pillars of the backbone, conferring ar ich topological diversity.…”

“…The main building blocks of G‐Quadruplexes (DNA as well as RNA) are constituted of guanine tetrads (G 4 ), held together by Hoogsteen‐type hydrogen bonds (Figure ). Two or more tetrads can stack on top of each other due to the contribution of electrostatic and dispersion forces . Sugar‐phosphate moieties of guanosine monomers constitute the outer backbone of these structures and contribute to their stability (Figure ).…”

Quantum Mechanical Investigation of the G-Quadruplex Systems of Human Telomere

“…This optimization has as a consequence the increase of the atomic charges of the atoms involved in the H-bridges around the cavity and of the H-bonds strength. This optimization is not used in general in the literature, as demonstrated in ref (54).…”

“…In particular, we have optimized only the two G-quartets of these systems and kept fixed the position of the backbones according to those of the experimental data. At this point, we would like to stress that the authors of ref (54) have optimized only the hydrogen atoms from the structures extracted from the PDB. In our opinion, this type of optimization is not sufficient because the changing of the quadruplex cavity is essential in the study of the ion inclusion.…”

“…Only in ref (51), for the first time, as underlined by the authors, accurate QM computations (DFT-D3 with large atomic orbital basis sets) have been applied to these systems. Recently, QM calculations on dimers of G-quartet systems have been utilized to verify and parameterize the MD simulations, 52 to study the stabilization with different cations, 53 and the DFT-D3 method is applied to three-stack models 54 cutting from 2O4F and JPQ in PDB (Protein Data Bank). The authors of this study find stronger hydrogen-bonding and stacking interactions in the stem of the parallel G-quadruplex (2O4F), compared to those in the antiparallel system (JPQ).…”