The structural impact of DNA mismatches

Abstract

The structure and dynamics of all the transversion and transition mismatches in three different DNA environments have been characterized by molecular dynamics simulations and NMR spectroscopy. We found that the presence of mismatches produced significant local structural alterations, especially in the case of purine transversions. Mismatched pairs often show promiscuous hydrogen bonding patterns, which interchange among each other in the nanosecond time scale. This therefore defines flexible base pairs, where breathing is frequent, and where distortions in helical parameters are strong, resulting in significant alterations in groove dimension. Even if the DNA structure is plastic enough to absorb the structural impact of the mismatch, local structural changes can be propagated far from the mismatch site, following the expected through-backbone and a previously unknown through-space mechanism. The structural changes related to the presence of mismatches help to understand the different susceptibility of mismatches to the action of repairing proteins.

A novel conception for spontaneous transversions caused by homo-pyrimidine DNA mismatches: a QM/QTAIM highlight

“…Our data are in a good agreement with other theoretical calculations [28]. Thus, fixation in the DNA duplex of the C·C(w) mispair, stabilized by the N4H···N3 H-bond and N3···O2 van der Waals contact, and the T·T(w) mismatch, joined by the N3H···O4 and N3H···O2 H-bonds (Table S1) (Figs.…”

“…Our findings also add substantially to the understanding, why the pyrimidine·pyrimidine T·T(w) mismatches are much better deleted from the genome by the reparation systems "sharpened" for the wobble architecture than the C·C(w) mispairs (see works [28,63] Table 1. Energetic and kinetic characteristics of the T·T(w)↔T·T*(WC), T·T(w)↔T* O2 ·T(WC), T* O2 ·T(w)↔T·T* O2 (WC), T·T(w)↔T*·T* O2 (w), C·C(w)↔C·C*(WC), C·C*(WC)↔C*·C*(w) and C*·C*(w)↔C* O2 ·C(w) tautomerisations via the sequential DPT accompanied by the structural rearrangement of the base pair obtained at the MP2/cc-pVQZ//B3LYP/6-311++G(d,p) level of theory (see also Figs.…”

“…3 and 6). This finding can't be reflected by the MD calculations operating solely with the canonical tautomers [28].…”

Sequence‐Specific Covalent Capture Coupled with High‐Contrast Nanopore Detection of a Disease‐Derived Nucleic Acid Sequence

“…The exact location of the cross-link generated between our first-generation probe and the wild-type sequence was uncertain, but we suspected that flexibility introduced by the T-T mispair [9] enabled cross-link formation between the Ap site and the directly opposing guanine residue. [10] Accordingly, we prepared a new probe strand containing an adenine residue on the 3’-side of the Ap site, such that the probe was complementary to the wild-type BRAF sequence (duplex D , Fig.…”

Multiscale simulation of DNA

“…The number of studies in this section is also endless, and we will cite those that might have had a larger impact in the understanding of the biology of modified DNAs. From this point of view, it is worth mentioning the works on the impact of the oxidization or deamination of guanine [89][90][91][92] on the properties and repairing mechanisms of DNA, as well as the studies on the DNA mismatches [93,94], or the UV-damaged DNAs [95,96].…”