Nejvíce citovaný článek - PubMed ID 26605732
A Novel Approach for Deriving Force Field Torsion Angle Parameters Accounting for Conformation-Dependent Solvation Effects
The transition from B-DNA to A-DNA occurs in many protein-DNA interactions or in DNA/RNA hybrid duplexes, and thus plays a role in many important biomolecular processes that convey the biological function of DNA. However, the stability of A-DNA is severely underestimated in current AMBER force fields such as OL15, OL21 or bsc1, potentially leading to unstable or deformed protein-DNA complexes. In this study, we refine the deoxyribose dihedral potential to increase the stability of the north (N) puckering present in A-DNA. The new parameters, termed OL24, model A/B equilibrium in B-DNA duplexes in water in good agreement with nuclear magnetic resonance (NMR) experiment. They also improve the description of DNA/RNA hybrids and the transition of the DNA duplex to the A-form in concentrated ethanol solutions. These refinements significantly improve the modeling of protein-DNA complexes, increasing their structural stability and A-form population, while maintaining accurate representation of canonical B-DNA duplexes. Overall, the new parameters should allow more reliable modeling of the thermodynamic equilibrium between A- and B-DNA forms and the interactions of DNA with proteins.
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. Here we use extensive all-atom molecular dynamics simulations to parameterize a model of kink-turn in which the two flanking helical stems are represented by effective rigid bodies. Time series of the full set of six interhelical coordinates enable us to extract minimum energy shapes and harmonic stiffness constants for kink-turns from different RNA functional classes. The analysis suggests that kink-turns exhibit isotropic bending stiffness but are highly anisotropic with respect to lateral displacement of the stems. The most flexible lateral displacement mode is perpendicular to the plane of the static bend. These results may help understand the structural adaptation and mechanical signal transmission by kink-turns in complex natural and artificial RNA structures.
- MeSH
- konformace nukleové kyseliny MeSH
- ribozomy metabolismus MeSH
- RNA * chemie MeSH
- simulace molekulární dynamiky * MeSH
- vazebná místa MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- RNA * MeSH
Bone remodeling is a fine-tuned process principally regulated by a cascade triggered by interaction of receptor activator of NF-κB (RANK) and RANK ligand (RANKL). Excessive activity of the RANKL gene leads to increased bone resorption and can influence the incidence of osteoporosis. Although much has been learned about the intracellular signals activated by RANKL/RANK complex, significantly less is known about the molecular mechanisms of regulation of RANKL expression. Here, we report on the structure of an unprecedented DNA G-quadruplex, well-known secondary structure-mediated gene expression regulator, formed by a G-rich sequence found in the regulatory region of a RANKL gene. Solution-state NMR structural study reveals the formation of a three-layered parallel-type G-quadruplex characterized by an unique features, including a G-A bulge. Although a guanine within a G-tract occupies syn glycosidic conformation, bulge-forming residues arrange in a pseudo-loop conformation to facilitate partial 5/6-ring stacking, typical of G-quadruplex structures with parallel G-tracts orientation. Such distinctive structural features protruding from the core of the structure can represent a novel platform for design of highly specific ligands with anti-osteoporotic function. Additionally, our study suggests that the expression of RANKL gene may be regulated by putative folding of its G-rich region into non-B-DNA structure(s).
- Klíčová slova
- G-quadruplex, NMR spectroscopy, osteoporosis, structure,
- MeSH
- adenin chemie MeSH
- G-kvadruplexy MeSH
- guanin chemie MeSH
- konformace nukleové kyseliny MeSH
- lidé MeSH
- ligand RANK genetika MeSH
- nukleární magnetická rezonance biomolekulární MeSH
- osteoporóza genetika MeSH
- protein RANK genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- adenin MeSH
- guanin MeSH
- ligand RANK MeSH
- protein RANK MeSH
- TNFRSF11A protein, human MeSH Prohlížeč
- TNFSF11 protein, human MeSH Prohlížeč
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.
- MeSH
- DNA chemie MeSH
- katalýza MeSH
- konformace nukleové kyseliny * MeSH
- počítačová simulace MeSH
- RNA chemie MeSH
- simulace molekulární dynamiky * MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- DNA MeSH
- RNA MeSH
We present a refinement of the backbone torsion parameters ε and ζ of the Cornell et al. AMBER force field for DNA simulations. The new parameters, denoted as εζOL1, were derived from quantum-mechanical calculations with inclusion of conformation-dependent solvation effects according to the recently reported methodology (J. Chem. Theory Comput. 2012, 7(9), 2886-2902). The performance of the refined parameters was analyzed by means of extended molecular dynamics (MD) simulations for several representative systems. The results showed that the εζOL1 refinement improves the backbone description of B-DNA double helices and G-DNA stem. In B-DNA simulations, we observed an average increase of the helical twist and narrowing of the major groove, thus achieving better agreement with X-ray and solution NMR data. The balance between populations of BI and BII backbone substates was shifted towards the BII state, in better agreement with ensemble-refined solution experimental results. Furthermore, the refined parameters decreased the backbone RMS deviations in B-DNA MD simulations. In the antiparallel guanine quadruplex (G-DNA) the εζOL1 modification improved the description of non-canonical α/γ backbone substates, which were shown to be coupled to the ε/ζ torsion potential. Thus, the refinement is suggested as a possible alternative to the current ε/ζ torsion potential, which may enable more accurate modeling of nucleic acids. However, long-term testing is recommended before its routine application in DNA simulations.
- Publikační typ
- časopisecké články MeSH
