Temperature-dependent elasticity of DNA, RNA, and hybrid double helices.

Nucleic acid double helices in their DNA, RNA, and DNA-RNA hybrid form play a fundamental role in biology and are main building blocks of artificial nanostructures, but how their properties depend on temperature remains poorly understood. Here, we report thermal dependence of dynamic bending persistence length, twist rigidity, stretch modulus, and twist-stretch coupling for DNA, RNA, and hybrid duplexes between 7°C and 47°C. The results are based on all-atom molecular dynamics simulations using different force field parameterizations.

Temperature-Dependent Twist of Double-Stranded RNA Probed by Magnetic Tweezer Experiments and Molecular Dynamics Simulations.

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.

RNA kink-turns are highly anisotropic with respect to lateral displacement of the flanking stems.

Kink-turns are highly bent internal loop motifs commonly found in the ribosome and other RNA complexes. They frequently act as binding sites for proteins and mediate tertiary interactions in larger RNA structures. Kink-turns have been a topic of intense research, but their elastic properties in the folded state are still poorly understood.

Impact of the Nucleosome Histone Core on the Structure and Dynamics of DNA-Containing Pyrimidine-Pyrimidone (6-4) Photoproduct.

The pyrimidine-pyrimidone (6-4) photoproduct (64-PP) is an important photoinduced DNA lesion constituting a mutational signature for melanoma. The structural impact of 64-PP on DNA complexed with histones affects the lesion mutagenicity and repair but remains poorly understood. Here we investigate the conformational dynamics of DNA-containing 64-PP within the nucleosome core particle by atomic-resolution molecular dynamics simulations and multiscale data analysis.

Compensatory Mechanisms in Temperature Dependence of DNA Double Helical Structure: Bending and Elongation.

Changes in the structure of double-stranded (ds) DNA with temperature affect processes in thermophilic organisms and are important for nanotechnological applications. Here we investigate temperature-dependent conformational changes of dsDNA at the scale of several helical turns and at the base pair step level, inferred from extensive all-atom molecular dynamics simulations of DNA at temperatures from 7 to 47 °C. Our results suggest that, contrary to twist, the overall bending of dsDNA without A-tracts depends only very weakly on temperature, due to the mutual compensation of directional local bends.

The temperature dependence of the helical twist of DNA.

DNA is the carrier of all cellular genetic information and increasingly used in nanotechnology. Quantitative understanding and optimization of its functions requires precise experimental characterization and accurate modeling of DNA properties. A defining feature of DNA is its helicity.

rRNA C-Loops: Mechanical Properties of a Recurrent Structural Motif.

C-loop is an internal loop motif found in the ribosome and used in artificial nanostructures. While its geometry has been partially characterized, its mechanical properties remain elusive. Here we propose a method to evaluate global shape and stiffness of an internal loop.

Influence of BII Backbone Substates on DNA Twist: A Unified View and Comparison of Simulation and Experiment for All 136 Distinct Tetranucleotide Sequences.

Reliable representation of the B-DNA base-pair step twist is one of the crucial requirements for theoretical modeling of DNA supercoiling and other biologically relevant phenomena in B-DNA. It has long been suspected that the twist is inaccurately described by current empirical force fields. Unfortunately, comparison of simulation results with experiments is not straightforward because of the presence of BII backbone substates, whose populations may differ in experimental and simulation ensembles.

Interstrand cross-linking implies contrasting structural consequences for DNA: insights from molecular dynamics.

Oxidatively-generated interstrand cross-links rank among the most deleterious DNA lesions. They originate from abasic sites, whose aldehyde group can form a covalent adduct after condensation with the exocyclic amino group of purines, sometimes with remarkably high yields. We use explicit solvent molecular dynamics simulations to unravel the structures and mechanical properties of two DNA sequences containing an interstrand cross-link.

Long-timescale dynamics of the Drew-Dickerson dodecamer.

We present a systematic study of the long-timescale dynamics of the Drew-Dickerson dodecamer (DDD: d(CGCGAATTGCGC)2) a prototypical B-DNA duplex. Using our newly parameterized PARMBSC1 force field, we describe the conformational landscape of DDD in a variety of ionic environments from minimal salt to 2 M Na(+)Cl(-) or K(+)Cl(-) The sensitivity of the simulations to the use of different solvent and ion models is analyzed in detail using multi-microsecond simulations. Finally, an extended (10 μs) simulation is used to characterize slow and infrequent conformational changes in DDD, leading to the identification of previously uncharacterized conformational states of this duplex which can explain biologically relevant conformational transitions.

On the Use of Molecular Dynamics Simulations for Probing Allostery through DNA.

A recent study described an allosteric effect in which the binding of a protein to DNA is influenced by another protein bound nearby. The effect shows a periodicity of ∼10 basepairs and decays with increasing protein-protein distance. As a mechanistic explanation, the authors reported a similar periodic, decaying pattern of the correlation coefficient between major groove widths inferred from a shorter molecular dynamics simulation.

Explaining the striking difference in twist-stretch coupling between DNA and RNA: A comparative molecular dynamics analysis.

Double stranded helical DNA and RNA are flexible molecules that can undergo global conformational fluctuations. Their bending, twisting and stretching deformabilities are of similar magnitude. However, recent single-molecule experiments revealed a striking qualitative difference indicating an opposite sign for the twist-stretch couplings of dsDNA and dsRNA [Lipfert et al.

Mechanical Model of DNA Allostery.

The importance of allosteric effects in DNA is becoming increasingly appreciated, but the underlying mechanisms remain poorly understood. In this work, we propose a general modeling framework to study DNA allostery. We describe DNA in a coarse-grained manner by intra-base pair and base pair step coordinates, complemented by groove widths.

Multiscale modelling of DNA mechanics.

Mechanical properties of DNA are important not only in a wide range of biological processes but also in the emerging field of DNA nanotechnology. We review some of the recent developments in modeling these properties, emphasizing the multiscale nature of the problem. Modern atomic resolution, explicit solvent molecular dynamics simulations have contributed to our understanding of DNA fine structure and conformational polymorphism.

Insights into the structure of intrastrand cross-link DNA lesion-containing oligonucleotides: G[8-5m]T and G[8-5]C from molecular dynamics simulations.

Oxidatively generated complex DNA lesions occur more rarely than single-nucleotide defects, yet they play an important role in carcinogenesis and aging diseases because they have proved to be more mutagenic than simple lesions. Whereas their formation pathways are rather well understood, the field suffers from the absence of structural data that are crucial for interpreting the lack of repair. No experimental structures are available for oligonucleotides featuring such a lesion.

μABC: a systematic microsecond molecular dynamics study of tetranucleotide sequence effects in B-DNA.

We present the results of microsecond molecular dynamics simulations carried out by the ABC group of laboratories on a set of B-DNA oligomers containing the 136 distinct tetranucleotide base sequences. We demonstrate that the resulting trajectories have extensively sampled the conformational space accessible to B-DNA at room temperature. We confirm that base sequence effects depend strongly not only on the specific base pair step, but also on the specific base pairs that flank each step.

Effect O6-guanine alkylation on DNA flexibility studied by comparative molecular dynamics simulations.

Alkylation of guanine at the O6 atom is a highly mutagenic DNA lesion because it alters the coding specificity of the base causing G:C to A:T transversion mutations. Specific DNA repair enzymes, e.g.

Base Pair Fraying in Molecular Dynamics Simulations of DNA and RNA.

Terminal base pairs of DNA and RNA molecules in solution are known to undergo frequent transient opening events (fraying). Accurate modeling of this process is important because of its involvement in nucleic acid end recognition and enzymatic catalysis. In this article, we describe fraying in molecular dynamics simulations with the ff99bsc0, ff99bsc0χOL3, and ff99bsc0χOL4 force fields, both for DNA and RNA molecules.

Mechanical properties of symmetric and asymmetric DNA A-tracts: implications for looping and nucleosome positioning.

A-tracts are functionally important DNA sequences which induce helix bending and have peculiar structural properties. While A-tract structure has been qualitatively well characterized, their mechanical properties remain controversial. A-tracts appear structurally rigid and resist nucleosome formation, but seem flexible in DNA looping.

Structure, dynamics, and interactions of a C4'-oxidized abasic site in DNA: a concomitant strand scission reverses affinities.

Apurinic/apyrimidinic (AP) sites constitute the most frequent form of DNA damage. They have proven to produce oxidative interstrand cross-links, but the structural mechanism of cross-link formation within a DNA duplex is poorly understood. In this work, we study three AP-containing d[GCGCGCXCGCGCG]·d[CGCGCGKGCGCGC] duplexes, where X = C, A, or G and K denotes an α,β-unsaturated ketoaldehyde derived from elimination of a C4'-oxidized AP site featuring a 3' single-strand break.

Effect of 8-oxoguanine on DNA structure and deformability.

8-Oxoguanine (oxoG) is an abundant product of oxidative DNA damage. It is removed by repair glycosylases, but exactly how the enzymes recognize oxoG in the large surplus of undamaged bases is not fully understood. The lesion may induce changes in the properties of naked DNA that facilitate the recognition.

Structure, Stiffness and Substates of the Dickerson-Drew Dodecamer.

The Dickerson-Drew dodecamer (DD) d-[CGCGAATTCGCG] is a prototypic B-DNA molecule whose sequence-specific structure and dynamics have been investigated by many experimental and computational studies. Here, we present an analysis of DD properties based on extensive atomistic molecular dynamics (MD) simulations using different ionic conditions and water models. The 0.

Strikingly different effects of hydrogen bonding on the photodynamics of individual nucleobases in DNA: comparison of guanine and cytosine.

Ab initio surface hopping dynamics calculations were performed to study the photophysical behavior of cytosine and guanine embedded in DNA using a quantum mechanical/molecular mechanics (QM/MM) approach. It was found that the decay rates of photo excited cytosine and guanine were affected in a completely different way by the hydrogen bonding to the DNA environment. In case of cytosine, the geometrical restrictions exerted by the hydrogen bonds did not influence the relaxation time of cytosine significantly due to the generally small cytosine ring puckering required to access the crossing region between excited and ground state.

Can We Accurately Describe the Structure of Adenine Tracts in B-DNA? Reference Quantum-Chemical Computations Reveal Overstabilization of Stacking by Molecular Mechanics.

Sequence-dependent local variations of helical parameters, structure, and flexibility are crucial for molecular recognition processes involving B-DNA. A-tracts, i.e.