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

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.