Although current AMBER force fields are relatively accurate for canonical B-DNA, many noncanonical structures are still described incorrectly. As noncanonical motifs are attracting increasing attention due to the role they play in living organisms, further improvement is desirable. Here, we have chosen the Z-DNA molecule, which can be considered a touchstone of the universality of empirical force fields, since the noncanonical α and γ backbone conformations native to Z-DNA are also found in protein-DNA complexes, i-motif DNA, and other noncanonical DNAs. We show that spurious α/γ conformations occurring in simulations with current AMBER force fields, OL15 and bsc1, are largely due to inaccurate α/γ parametrization. Moreover, stabilization of native Z-DNA substates involving γ = trans conformations appears to be in conflict with the correct description of the canonical B-DNA structure. Because the balance of the native and spurious conformations is influenced by nonadditive effects, this is a difficult case for an additive dihedral energy scheme such as AMBER. We propose new α/γ parameters, denoted OL21, and show that they improve the stability of native α/γ Z-DNA substates while keeping the canonical DNA description virtually unchanged, thus representing a reasonable compromise within the additive force field framework. Although further extensive testing is needed, the new modification appears to be a promising step toward a more reliable description of noncanonical DNA motifs and provides the best performance for Z-DNA molecules among current AMBER force fields.
- MeSH
- B-DNA chemie MeSH
- konformace nukleové kyseliny MeSH
- simulace molekulární dynamiky MeSH
- Z-DNA * MeSH
- Publikační typ
- časopisecké články MeSH
With both catalytic and genetic functions, ribonucleic acid (RNA) is perhaps the most pluripotent chemical species in molecular biology, and its functions are intimately linked to its structure and dynamics. Computer simulations, and in particular atomistic molecular dynamics (MD), allow structural dynamics of biomolecular systems to be investigated with unprecedented temporal and spatial resolution. We here provide a comprehensive overview of the fast-developing field of MD simulations of RNA molecules. We begin with an in-depth, evaluatory coverage of the most fundamental methodological challenges that set the basis for the future development of the field, in particular, the current developments and inherent physical limitations of the atomistic force fields and the recent advances in a broad spectrum of enhanced sampling methods. We also survey the closely related field of coarse-grained modeling of RNA systems. After dealing with the methodological aspects, we provide an exhaustive overview of the available RNA simulation literature, ranging from studies of the smallest RNA oligonucleotides to investigations of the entire ribosome. Our review encompasses tetranucleotides, tetraloops, a number of small RNA motifs, A-helix RNA, kissing-loop complexes, the TAR RNA element, the decoding center and other important regions of the ribosome, as well as assorted others systems. Extended sections are devoted to RNA-ion interactions, ribozymes, riboswitches, and protein/RNA complexes. Our overview is written for as broad of an audience as possible, aiming to provide a much-needed interdisciplinary bridge between computation and experiment, together with a perspective on the future of the field.
We provide a critical assessment of explicit-solvent atomistic molecular dynamics (MD) simulations of RNA and protein/RNA complexes, written primarily for non-specialists with an emphasis to explain the limitations of MD. MD simulations can be likened to hypothetical single-molecule experiments starting from single atomistic conformations and investigating genuine thermal sampling of the biomolecules. The main advantage of MD is the unlimited temporal and spatial resolution of positions of all atoms in the simulated systems. Fundamental limitations are the short physical time-scale of simulations, which can be partially alleviated by enhanced-sampling techniques, and the highly approximate atomistic force fields describing the simulated molecules. The applicability and present limitations of MD are demonstrated on studies of tetranucleotides, tetraloops, ribozymes, riboswitches and protein/RNA complexes. Wisely applied simulations respecting the approximations of the model can successfully complement structural and biochemical experiments. WIREs RNA 2017, 8:e1405. doi: 10.1002/wrna.1405 For further resources related to this article, please visit the WIREs website.
- MeSH
- konformace nukleové kyseliny MeSH
- lidé MeSH
- proteiny vázající RNA chemie metabolismus MeSH
- RNA chemie metabolismus MeSH
- simulace molekulární dynamiky * MeSH
- výpočetní biologie metody MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
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. In this work, we provide a comprehensive view of the effect of BII substates on the overall B-DNA helix twist and show how to reliably compare twist values from experiment and simulation in two scenarios. First, for longer DNA segments freely moving in solution, we show that sequence-averaged twists of different BI/BII ensembles can be compared directly because of approximate cancellation of the opposing BII effects. Second, for sequence-specific data, such as a particular base-pair step or tetranucleotide twist, can be compared only for a clearly defined BI/BII backbone conformation. For the purpose of force field testing, we designed a compact set of fourteen 22-base-pair B-DNA duplexes (Set 14) containing all 136 distinct tetranucleotide sequences and carried out a total of 84 μs of molecular dynamics simulations, primarily with the OL15 force field. Our results show that the ff99bsc0εζOL1χOL4, parmbsc1, and OL15 force fields model the B-DNA helical twist in good agreement with X-ray and minicircle ligation experiments. The comprehensive understanding obtained regarding the effect of BII substates on the base-pair step geometry should aid meaningful comparisons of various conformational ensembles in future research.
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. Here we show that in a state-of-the-art, microsecond-long simulation of the same DNA sequence, the periodicity of the correlation coefficient is not observed. To study the problem further, we extend an earlier mechanical model of DNA allostery based on constrained minimization of effective quadratic deformation energy of the DNA. We demonstrate that, if the constraints mimicking the bound proteins are properly applied, the periodicity in the binding energy is indeed recovered.
Recent advances in polarizable force fields have revealed that major reparameterization is necessary when the polarization energy is treated explicitly. This study is focused on the torsional parameters, which are crucial for the accurate description of conformational equilibria in biomolecules. In particular, attention is paid to the influence of polarization on the (i) transferability of dihedral terms between molecules, (ii) transferability between different environments, and (iii) additivity of dihedral energies. To this end, three polarizable force fields based on the induced point dipole model designed for use in AMBER are tested, including two recent ff02 reparameterizations. Attention is paid to the contributions due to short range interactions (1-2, 1-3, and 1-4) within the four atoms defining the dihedral angle. The results show that when short range 1-2 and 1-3 polarization interactions are omitted, as for instance in ff02, the 1-4 polarization contribution is rather small and unlikely to improve the description of the torsional energy. Conversely, when screened 1-2 and 1-3 interactions are included, the polarization contribution is sizeable and shows potential to improve the transferability of parameters between different molecules and environments as well as the additivity of dihedral terms. However, to reproduce intramolecular polarization effects accurately, further fine-tuning of the short range damping of polarization is necessary.
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. In this work, we investigate mechanical properties of symmetric AnTn and asymmetric A2n tracts for n = 3, 4, 5 using two types of coarse-grained models. The first model represents DNA as an ensemble of interacting rigid bases with non-local quadratic deformation energy, the second one treats DNA as an anisotropically bendable and twistable elastic rod. Parameters for both models are inferred from microsecond long, atomic-resolution molecular dynamics simulations. We find that asymmetric A-tracts are more rigid than the control G/C-rich sequence in localized distortions relevant for nucleosome formation, but are more flexible in global bending and twisting relevant for looping. The symmetric tracts, in contrast, are more rigid than asymmetric tracts and the control, both locally and globally. Our results can reconcile the contradictory stiffness data on A-tracts and suggest symmetric A-tracts to be more efficient in nucleosome exclusion than the asymmetric ones. This would open a new possibility of gene expression manipulation using A-tracts.
In this review primarily written for non-experts we explain basic methodological aspects and interpretation of modern quantum chemical (QM) computations applied to nucleic acids. We introduce current reference QM computations on small model systems consisting of dozens of atoms. Then we comment on recent advance of fast and accurate dispersion-corrected density functional theory methods, which will allow computations of small but complete nucleic acids building blocks in the near future. The qualitative difference between QM and molecular mechanics (MM, force field) computations is discussed. We also explain relation of QM and molecular simulation computations to experiments.
Base stacking is a major interaction shaping up and stabilizing nucleic acids. During the last decades, base stacking has been extensively studied by experimental and theoretical methods. Advanced quantum-chemical calculations clarified that base stacking is a common interaction, which in the first approximation can be described as combination of the three most basic contributions to molecular interactions, namely, electrostatic interaction, London dispersion attraction and short-range repulsion. There is not any specific π-π energy term associated with the delocalized π electrons of the aromatic rings that cannot be described by the mentioned contributions. The base stacking can be rather reasonably approximated by simple molecular simulation methods based on well-calibrated common force fields although the force fields do not include nonadditivity of stacking, anisotropy of dispersion interactions, and some other effects. However, description of stacking association in condensed phase and understanding of the stacking role in biomolecules remain a difficult problem, as the net base stacking forces always act in a complex and context-specific environment. Moreover, the stacking forces are balanced with many other energy contributions. Differences in definition of stacking in experimental and theoretical studies are explained.
Hybrid QM/MM methods combine the rigor of quantum mechanical (QM) calculations with the low computational cost of empirical molecular mechanical (MM) treatment allowing to capture dynamic properties to probe critical atomistic details of enzyme reactions. Catalysis by RNA enzymes (ribozymes) has only recently begun to be addressed with QM/MM approaches and is thus still a field under development. This review surveys methodology as well as recent advances in QM/MM applications to RNA mechanisms, including those of the HDV, hairpin, and hammerhead ribozymes, as well as the ribosome. We compare and correlate QM/MM results with those from QM and/or molecular dynamics (MD) simulations, and discuss scope and limitations with a critical eye on current shortcomings in available methodologies and computer resources. We thus hope to foster mutual appreciation and facilitate collaboration between experimentalists and theorists to jointly advance our understanding of RNA catalysis at an atomistic level.
- MeSH
- biofyzika metody MeSH
- fosfáty chemie MeSH
- fosforylace MeSH
- hořčík chemie MeSH
- katalýza MeSH
- konformace nukleové kyseliny MeSH
- kvantová teorie MeSH
- lidé MeSH
- molekulární modely MeSH
- počítačová simulace MeSH
- ribozomy chemie MeSH
- RNA katalytická chemie MeSH
- RNA virová chemie MeSH
- RNA chemie MeSH
- software MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
- Research Support, N.I.H., Extramural MeSH
