The structure and deformability of double-stranded DNA and RNA depend on the sequence of bases, affecting biological processes and nanostructure design, but this dependence is incompletely understood. Here we present mechanical properties of DNA and RNA duplexes inferred from atomic-resolution, explicit-solvent molecular dynamics (MD) simulations of 107 DNA and 107 RNA oligomers containing all hexanucleotide sequences. In addition to the level of rigid bases, minor and major grooves, we probe the length and sequence dependence of global material constants such as persistence lengths, stretching and twisting rigidities. We propose a simple model to predict sequence-dependent shape and nonlocal, harmonic stiffness for an arbitrary sequence, validate it on an independent set of MD simulations for DNA and RNA duplexes containing all pentamers, and demonstrate its utility in various applications. The large amount of the simulated data enabled us to study rare events, such as base-pair opening, or flips of the A-RNA sugar pucker into the B domain and the related dynamics of the 2'-OH group. Together, this work provides a comprehensive sequence-specific description of DNA and RNA duplex mechanics, forming a baseline for further research and allowing for a broad range of applications.

• MeSH
• DNA * chemistry   MeSH
• Nucleic Acid Conformation MeSH
• RNA * chemistry   MeSH
• Base Sequence MeSH
• Molecular Dynamics Simulation MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• DNA * MeSH
• RNA * MeSH

Histone post-translational modifications promote a chromatin environment that controls transcription, DNA replication and repair, but surprisingly few phosphorylations have been documented. We report the discovery of histone H3 serine-57 phosphorylation (H3S57ph) and show that it is implicated in different DNA repair pathways from fungi to vertebrates. We identified CHK1 as a major human H3S57 kinase, and disrupting or constitutively mimicking H3S57ph had opposing effects on rate of recovery from replication stress, 53BP1 chromatin binding, and dependency on RAD52. In fission yeast, mutation of all H3 alleles to S57A abrogated DNA repair by both non-homologous end-joining and homologous recombination, while cells with phospho-mimicking S57D alleles were partly compromised for both repair pathways, presented aberrant Rad52 foci and were strongly sensitised to replication stress. Mechanistically, H3S57ph loosens DNA-histone contacts, increasing nucleosome mobility, and interacts with H3K56. Our results suggest that dynamic phosphorylation of H3S57 is required for DNA repair and recovery from replication stress, opening avenues for investigating the role of this modification in other DNA-related processes.

• MeSH
• Chromatin MeSH
• Phosphorylation MeSH
• Histones * MeSH
• Humans MeSH
• DNA Repair MeSH
• Protein Processing, Post-Translational MeSH
• Influenza A virus * MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Chromatin MeSH
• Histones * MeSH

Mismatch repair is a highly conserved cellular pathway responsible for repairing mismatched dsDNA. Errors are detected by the MutS enzyme, which most likely senses altered mechanical property of damaged dsDNA rather than a specific molecular pattern. While the curved shape of dsDNA in crystallographic MutS/DNA structures suggests the role of DNA bending, the theoretical support is not fully convincing. Here, we present a computational study focused on a base-pair opening into the minor groove, a specific base-pair motion observed upon interaction with MutS. Propensities for the opening were evaluated in terms of two base-pair parameters: Opening and Shear. We tested all possible base pairs in anti/anti, anti/syn and syn/anti orientations and found clear discrimination between mismatches and canonical base-pairs only for the opening into the minor groove. Besides, the discrimination gap was also confirmed in hotspot and coldspot sequences, indicating that the opening could play a more significant role in the mismatch recognition than previously recognized. Our findings can be helpful for a better understanding of sequence-dependent mutability. Further, detailed structural characterization of mismatches can serve for designing anti-cancer drugs targeting mismatched base pairs.

• MeSH
• Base Pair Mismatch * MeSH
• DNA chemistry   metabolism   MeSH
• DNA Mismatch Repair * MeSH
• Base Pairing MeSH
• Molecular Dynamics Simulation * MeSH
• Thermodynamics MeSH
• MutS DNA Mismatch-Binding Protein chemistry   genetics   metabolism   MeSH
• Hydrogen Bonding MeSH
• Computational Biology MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• DNA MeSH
• MutS DNA Mismatch-Binding Protein MeSH

Adenosine to inosine (A⁻I) editing is the most common modification of double-stranded RNA (dsRNA). This change is mediated by adenosine deaminases acting on RNA (ADARs) enzymes with a preference of U>A>C>G for 5′ neighbor and G>C=A>U or G>C>U=A for 3′ neighbor. A⁻I editing occurs most frequently in the non-coding regions containing repetitive elements such as ALUs. It leads to disruption of RNA duplex structure, which prevents induction of innate immune response. We employed standard and biased molecular dynamics (MD) simulations to analyze the behavior of RNA duplexes with single and tandem inosine⁻uracil (I⁻U) base pairs in different sequence context. Our analysis showed that the I⁻U pairs induce changes in base pair and base pair step parameters and have different dynamics when compared with standard canonical base pairs. In particular, the first I⁻U pair from tandem I⁻U/I⁻U systems exhibited increased dynamics depending on its neighboring 5′ base. We discovered that UII sequence, which is frequently edited, has lower flexibility compared with other sequences (AII, GII, CII), hence it only modestly disrupts dsRNA. This might indicate that the UAA motifs in ALUs do not have to be sufficiently effective in preventing immune signaling.

• Keywords
• I-U base pairs, adenosine to inosine editing, dsRNA, molecular dynamics simulations,
• Publication type
• Journal Article MeSH

The utility of molecular dynamics (MD) simulations to model biomolecular structure, dynamics, and interactions has witnessed enormous advances in recent years due to the availability of optimized MD software and access to significant computational power, including GPU multicore computing engines and other specialized hardware. This has led researchers to routinely extend conformational sampling times to the microsecond level and beyond. The extended sampling time has allowed the community not only to converge conformational ensembles through complete sampling but also to discover deficiencies and overcome problems with the force fields. Accuracy of the force fields is a key component, along with sampling, toward being able to generate accurate and stable structures of biopolymers. The Amber force field for nucleic acids has been used extensively since the 1990s, and multiple artifacts have been discovered, corrected, and reassessed by different research groups. We present a direct comparison of two of the most recent and state-of-the-art Amber force field modifications, bsc1 and OL15, that focus on accurate modeling of double-stranded DNA. After extensive MD simulations with five test cases and two different water models, we conclude that both modifications are a remarkable improvement over the previous bsc0 force field. Both force field modifications show better agreement when compared to experimental structures. To ensure convergence, the Drew-Dickerson dodecamer (DDD) system was simulated using 100 independent MD simulations, each extended to at least 10 μs, and the independent MD simulations were concatenated into a single 1 ms long trajectory for each combination of force field and water model. This is significantly beyond the time scale needed to converge the conformational ensemble of the internal portions of a DNA helix absent internal base pair opening. Considering all of the simulations discussed in the current work, the MD simulations performed to assess and validate the current force fields and water models aggregate over 14 ms of simulation time. The results suggest that both the bsc1 and OL15 force fields render average structures that deviate significantly less than 1 Å from the average experimental structures. This can be compared to similar but less exhaustive simulations with the CHARMM 36 force field that aggregate to the ∼90 μs time scale and also perform well but do not produce structures as close to the DDD NMR average structures (with root-mean-square deviations of 1.3 Å) as the newer Amber force fields. On the basis of these analyses, any future research involving double-stranded DNA simulations using the Amber force fields should employ the bsc1 or OL15 modification.

• MeSH
• DNA, B-Form chemistry   MeSH
• DNA chemistry   MeSH
• Nucleic Acid Conformation MeSH
• Magnetic Resonance Spectroscopy MeSH
• Base Pairing MeSH
• Molecular Dynamics Simulation MeSH
• Water chemistry   MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• DNA, B-Form MeSH
• DNA MeSH
• Water MeSH