The pyrimidine-pyrimidone (6-4) photoproduct (64-PP) is an important photoinduced DNA lesion, which constitutes a mutational signature for melanoma. The structural impact of 64-PP on DNA complexed with compaction proteins, and notably histones, affects the mechanism of its mutagenicity and repair but remains poorly understood. Here we investigate the conformational dynamics of DNA containing 64-PP lesions within the nucleosome core particle by atomic-resolution molecular dynamics simulations at the multi-microsecond time scale. We demonstrate that the histone core exerts important mechanical restraints that largely decrease global DNA structural fluctuations. However, we also show that local DNA flexibility at the damaged site is enhanced, due to imperfect structural adaptation to restraints imposed by the histone core. In particular, if 64-PP faces the histone core and is therefore not directly accessible by the repair protein, the complementary strand facing the solvent exhibits higher flexibility than the corresponding strand in a naked, undamaged DNA. This may serve as an initial recognition signal for repair. Our simulations also pinpoint the structural role of proximal residues from the truncated histone tails.
The pyrimidine-pyrimidone (6-4) photoproduct (64-PP) is an important photoinduced DNA lesion, which constitutes a mutational signature for melanoma. The structural impact of 64-PP on DNA complexed with compaction proteins, and notably histones, affects the mechanism of its mutagenicity and repair but remains poorly understood. Here we investigate the conformational dynamics of DNA containing 64-PP lesions within the nucleosome core particle by atomic-resolution molecular dynamics simulations at the multi-microsecond time scale. We demonstrate that the histone core exerts important mechanical restraints that largely decrease global DNA structural fluctuations. However, we also show that local DNA flexibility at the damaged site is enhanced, due to imperfect structural adaptation to restraints imposed by the histone core. In particular, if 64-PP faces the histone core and is therefore not directly accessible by the repair protein, the complementary strand facing the solvent exhibits higher flexibility than the corresponding strand in a naked, undamaged DNA. This may serve as an initial recognition signal for repair. Our simulations also pinpoint the structural role of proximal residues from the truncated histone tails.
RNA plays critical roles in the transmission and regulation of genetic information and is increasingly used in biomedical and biotechnological applications. Functional RNAs contain extended double-stranded regions and the structure of double-stranded RNA (dsRNA) has been revealed at high-resolution. However, the dependence of the properties of the RNA double helix on environmental effects, notably temperature, is still poorly understood. Here, we use single-molecule magnetic tweezers measurements to determine the dependence of the dsRNA twist on temperature. We find that dsRNA unwinds with increasing temperature, even more than DNA, with ΔTwRNA = −14.4 +/- 0.7 deg/(degC.kbp), compared to ΔTwDNA = −11.0 +/- 1.2 deg/(degC.kbp). All-atom molecular dynamics (MD) simulations using a range of nucleic acid force fields, ion parameters, and water models correctly predict that dsRNA unwinds with rising temperature, but significantly underestimate the magnitude of the effect. These MD data, together with additional MD simulations involving DNA and DNA-RNA hybrid duplexes, reveal a linear correlation between twist temperature decrease and the helical rise, in line with DNA but at variance with RNA experimental data. We speculate that this discrepancy might be caused by some unknown bias in the RNA force fields tested, or by as yet undiscovered transient alternative structures in the RNA duplex. Our results provide a baseline to model more complex RNA assemblies and to test and develop new parameterizations for RNA simulations. They may also inspire physical models of temperature-dependent dsRNA structure.
The double-crossover (DX) motif is a key building block of DNA nanostructures. It connects two double helices by two closely spaced Holliday junctions. Despite its prominent importance, the structure and elasticity of the DX motif is not fully understood. Here we employ extensive all-atom molecular dynamics (MD) simulations of an antiparallel DNA DX motif with two full turns between crossovers to infer its global structure and deformability. We quantitatively reproduce the experimentally known two-fold increase of bending stiffness upon incorporation of a DNA duplex into the DX motif, and find out that its stretching and twisting stiffness are only slightly influenced. To further describe the motif, we define four effective rigid bodies, each involving several base pairs flanking the Holliday junctions from the outside, and consider internal coordinates capturing relative displacement and orientation of the bodies. Time series of the coordinates from MD then yield the global structure of the DX motif and its stiffness in the harmonic approximation.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.